Compositions and methods for the treatment of depression

Abstract

The present disclosure provides a method for treating major depressive disorder in a human patient, the patient being identified as positive for a biomarker signature, the method comprising administering to the patient in need thereof an effective amount of an antidepressant.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 298,060, filed January 10, 2022, which is incorporated by reference herein in its entirety.

[0002] FIELD OF THEINVENTION The present disclosure relates to methods for treating depression using antidepressants, where a patient is identified as biomarker signature positive. [Background technology]

[0003] Major depressive disorder (MDD) affects approximately 7-15% of the general population. MDD is associated with significant morbidity and mortality and is a leading cause of incapacity worldwide. Approximately one-third of patients fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment resistant depression (TRD). Such patients who benefit from oral antidepressants (AD) have a high relapse rate despite continued treatment.

[0004] The impact of TRD on patients' lives is difficult to adequately describe. Many patients have depressive episodes that last for years. Severely depressed patients lose the will to continue with their lives and suicide attempts increase seven-fold. Life expectancy is reduced by 10 years. In extreme cases, they are unable to manage basic personal needs such as bathing or feeding or caring for themselves, leaving these care entirely to their parents, spouses, etc. This affects not only the patients themselves, but also their families and those who depend on them. They also lose the ability to find pleasure in doing things they previously enjoyed, which robs people of the essence of life and what drives it. In effect, their life is taken away from them by TRD.

[0005] There remains a need for improved treatments for patients with depression, particularly those with TRD. Summary of the Invention

[0006] In some aspects, the disclosure relates to a method of treating depression in a human patient comprising administering an effective amount of an antidepressant to a patient in need thereof, wherein the patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

[0007] In yet further embodiments, a patient is identified as biomarker signature positive. In certain embodiments, a patient is identified as biomarker signature positive when a biological sample obtained from the patient is identified as having at least one of: (a) a level of CRP higher than a reference CRP level; and (b) (i) a level of TNF-α higher than a reference TNF-α level; and (ii) a level of sIL6R higher than a reference sIL6R level.

[0008] In certain embodiments, the antidepressant is selected from esketamine and aticaplant, or pharma- ceutically acceptable salts thereof.

[0009] In a further embodiment, the antidepressant is aticaplant or a pharma- ceutically acceptable salt thereof. In a particular embodiment, the patient has had an inadequate response to other antidepressant therapy prior to treatment with aticaplant or a pharma- ceutically acceptable salt thereof. In a further embodiment, the other antidepressant therapy comprises one or more second antidepressants. In a particular embodiment, the one or more second antidepressants comprise selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) therapy, or a combination thereof.

[0010] In further aspects, the patient has anhedonia, for example, the patient has high anhedonia as measured by a total score of ≧32 on the Snaith-Hamilton Pleasure Scale (SHAPS).

[0011] In still further aspects, the antidepressant is esketamine.Certain aspects have an induction phase, optionally followed by a maintenance phase, where the induction phase includes induction phase treatment sessions at a given frequency, and the maintenance phase includes maintenance phase treatment sessions that are administered less frequently to the patient.

[0012] In certain aspects, depression comprises major depressive disorder. In some aspects, the major depressive disorder is major depressive disorder accompanied by suicidal ideation or behavior. In further aspects, the major depressive disorder is treatment-resistant depression. [Brief description of the drawings]

[0013] [Figure 1] 1 shows the clinical trial design for Example 1. [Diagram 2] FIG. 1 is a line graph showing least squares mean change (±SE) in MADRS (Montgomerysis-Ausberg Depression Rating Scale) total score from baseline during the treatment period for the enriched intent-to-treat (eITT) analysis set. [Diagram 3] 13 is a plot showing MADRS total score change at 6 weeks of treatment for the enriched and complete populations: MMRM Results-Estimated LS Mean and comparison to placebo. [Figure 4] FIG. 13 is a line graph showing least squares mean change (±SE) in SHAPS (Snaith Hamilton Pleasure Scale) total score from baseline for the eITT analysis set. [Diagram 5]FIG. 13 is a plot showing SHAPS total score change at 6 weeks of treatment for the enriched and complete populations: MMRM (Mixed-effects Model for Repeated Measures) results--estimated LS means and comparison to placebo. [Figure 6] 1 is a line graph showing MADRS total scores over time for the eITT analysis set: Mean (±SE). [Figure 7A] FIG. 1 is a line graph showing MADRS total scores over time for the full intent-to-treat (fITT) analysis set: mean (±SE). [Figure 7B] Excerpt from Figure 7A for weeks 0 to 6 of treatment. [Figure 8] FIG. 13 is a line graph showing the percentage of subjects with MADRS total score:remission of depressive symptoms (total score≦10) during treatment for the eITT analysis set. [Figure 9] fLine graph showing MADRS total score: percentage of subjects with remission of depression symptoms (total score < 10) during treatment for the ITT analysis set. [Figure 10] FIG. 1 is a line graph showing MADRS total score during treatment: percentage of responders (≧30% improvement from baseline) for the eITT analysis set. [Figure 11] fLine graph showing MADRS total score during treatment: percentage of responders (≧30% improvement from baseline) for the ITT analysis set. [Figure 12] FIG. 1 is a line graph showing MADRS total score during treatment: percentage of responders (≧50% improvement from baseline) for the eITT analysis set. [Figure 13] fLine graph showing MADRS total score during treatment: percentage of responders (≧50% improvement from baseline) for the ITT analysis set. [Figure 14] SHAPS total score over time for the eITT analysis set: line graph showing mean (±SE). [Figure 15] SHAPS total score over time for the fITT analysis set: line graph showing mean (±SE). [Figure 16] Changes in MADRS from baseline according to severity of anhedonia are shown. [Figure 17A] FIG. 1 is a line graph showing MADRS change from baseline for patients with high anhedonia, i.e., SHAPS≧38. [Figure 17B] FIG. 1 is a line graph showing MADRS change from baseline in patients with low anhedonia, i.e., SHAPS<38. [Figure 18] FIG. 1 is a bar graph showing a comparison of MADRS in patients with low and high anhedonia. [Figure 19] 1 is a line graph showing the mean ASEX total score change from baseline. [Figure 20] 1 is a bar graph showing the mean ASEX item-level change total score change from baseline. [Figure 21] The study scheme of Example 2. All patients will continue oral antidepressant SSRI / SNRI throughout the study period. Additionally, approximately 34 elderly participants will be randomized. [Figure 22] The study scheme of Example 3. All patients will continue oral antidepressant SSRI / SNRI throughout the study period. Additionally, approximately 68 elderly participants will be randomized. [Figure 23] 1 is a bar graph showing the SHAPS Item:LS Mean Change from Baseline at Week 6 by Baseline SHAPS Total Score for the fITT Analysis Set. In this figure, from top to bottom, the bars alternate between placebo or Atticaplant. For example, the first bar refers to Atticaplant, the second bar refers to placebo, the third bar refers to Atticaplant, etc. [Figure 24]f Plot showing MADRS total score at week 6 by different subgroups for the ITT analysis set: LS mean difference (60%). In this plot, <17 indicates mild severity, 18-24 indicates mild to moderate severity, and 25-30 indicates moderate to severe. [Diagram 25] Figures 26A-26D show two-panel box plots of the effect of biomarker signature on patient response to treatment. Three MM biomarker signature positive patients (21% of MDD) responded with a 6.3 MADRS point difference at final DB compared to placebo, a 4.7 point improvement compared to their biomarker signature negative counterparts. Figures 26A-26D are plots summarizing the results of patient subtyping using a biomarker signature consisting of dynorphin levels alone. [Figure 26A] Graph of treatment effect and signature dominance in biomarker signature positive groups. [Figure 26B] Showing a signature effect at a delta level of 19.9 pg / mL (SigPos=DYN>19.9, 64% of the cohort). [Figure 26C] Showing a signature effect at a delta level of 30 pg / mL (SigPos=DYN>29.5, 48% of the cohort). [Figure 26D] At higher levels of dynorphin, the signature effect appears to be more variable (SigPos=DYN>48.7, 30% of the cohort). [Figure 27A] Figure 1 is a plot summarizing the results of patient subtyping using a biomarker signature using a combination of high dynorphin and 3MM subtypes. Graph of treatment effect and signature dominance in the biosignature positive group. One note is that the signature dominance defined by SigPos and SigNeg is not stable at higher cutoffs. [Figure 27B]1 is a plot summarizing the results of patient subtyping using a biomarker signature using a combination of high dynorphin and 3MM subtypes, showing that for biomarker signature negative patients (SigPos=3MM or DYN>19.9, 73% of the cohort), the interaction effect is significantly more pronounced due to a worse mean atticaplant response than placebo. [Figure 27C] FIG. 1 is a plot summarizing the results of patient subtyping using a biomarker signature using a combination of high dynorphin and 3MM subtypes. It shows that the effect of the biomarker signature is more stable at higher dynorphin cut points. SigPos=3MM or DYN>29.5, showing 61% of the cohort. [Figure 27D] FIG. 1 is a plot summarizing the results of patient subtyping using a biomarker signature using a combination of high dynorphin and 3MM subtypes. It shows that the effect of the biomarker signature is more stable at higher dynorphin cut points. SigPos=3MM or DYN>48.7, showing 48% of the cohort. [Figure 28A] 1 is a plot showing the results of patient subtyping using a biomarker signature using a combination of high dynorphin and 3MM subtypes. [Figure 28B] 1 is a plot showing the results of patient subtyping using a biomarker signature using a combination of high dynorphin and 3MM subtypes, showing a large treatment effect in biomarker signature positive patients and dominance of the large signature across a wide range of dynorphin levels (SigPos=(CRP>3&(IL6R>25|TNFα>4))&DYN>11.5). [Figure 29A]1 is a plot summarizing the results of patient subtyping using a biomarker signature using a combination of high dynorphin (δ1) or 3MM and intermediate dynorphin (δ2) subtypes, specifically, DYN>δ1pg / mL or (DYN>δ2pg / mL and CRP>3mg / L and (TNFα>4pg / mL or sIL6R>25ng / mL). 2 is a graph of the mean difference in response (MADRS) in EP for dynorphin levels in pg / mL. [Figure 29B] FIG. 13 is a plot summarizing the results of patient subtyping using a biomarker signature using a combination of high dynorphin (δ1) or 3MM with intermediate dynorphin (δ2) subtypes, specifically, DYN>δ1pg / mL or (DYN>δ2pg / mL and CRP>3mg / L and (TNFα>4pg / mL or sIL6R>25ng / mL). SigPos=DYN>24.0 or (3MM and DYN>8), showing 63% of the cohort. [Figure 29C] FIG. 13 is a plot summarizing the results of patient subtyping using a biomarker signature using a combination of high dynorphin (δ1) or 3MM with intermediate dynorphin (δ2) subtypes, specifically, DYN>δ1pg / mL or (DYN>δ2pg / mL and CRP>3mg / L and (TNFα>4pg / mL or sIL6R>25ng / mL). SigPos=DYN>50 or (3MM and DYN>8), showing 38% of the cohort. [Diagram 30] Figure 1 shows the study design of Example 1. Upon entry into the study, enrolled non-responder subjects continued to receive the same oral antidepressant that was started in the ESKETINTRD3005 study. New oral ADs are for direct entry subjects only. [Diagram 31] FIG. 1 shows the mean MADRS total score over time in the IND and OP / MA phases based on the observed case data of Example 1. [Diagram 32] FIG. 1 shows responses of patients with a response of >50% reduction from baseline and remission of MADRS <12. [Diagram 33]FIG. 1 shows the mean PHQ-9 total score over time in the IND and OP / MA phases based on the observed case data of Example 1. [Diagram 34] Shows 3MM efficacy across various clinical trials. For ESKETINTRD2003, only subjects who received consistent treatment across the two double-blind phases were considered. ClinicalTrials.gov identifiers for each of the illustrated trials are as follows: 54135419SUI3001 (NCT03039192); 54135419SUI3002 (NCT03097133); ESKETINSUI2001 (NCT02133001); 54135419TRD2005 (NCT02918318); ESKETINTRD2003 (NCT01998958); ESKETINTRD3001 (NCT02417064); and ESKETINTRD3002 (NCT02418585). [Diagram 35] The 3MM biomarker signature positive subjects (TE SigPos), biomarker signature negative subjects (TE SigNeg), and differences between subtypes (signature dominance) are shown for the various clinical trials. Overall, the treatment effect in 3MM+ patients in the final DB was 7.8 MADRS points, significantly greater than the treatment effect of 2.0 MADRS points in 3MM- patients (p<0.01). The effect was evident in three of the four TRD studies. In ESKETINTRD2003, only subjects who received consistent treatment across the two double-blind phases were considered. [Figure 36A] Graph showing change in MADRS for placebo (PBO) vs. treatment (TRT) biomarker signature positive patients in the ESKETINTRD2003 study. [Figure 36B] Graph showing change in MADRS for placebo (PBO) vs. treatment (TRT) biomarker signature negative patients in the ESKETINTRD2003 study. [Figure 37A] Showing 2MM effects across various clinical trials. [Figure 37B]Shown is 3MM efficacy across various clinical trials. High.Diff(PBO-TRT) refers to TE SigPos subjects, Other.Diff(PBO-TRT) refers to TE SigNeg subjects, and High.Diff-Other.Diff(PBO-TRT) refers to signature dominance. ClinicalTrials.gov identifiers for each of the illustrated trials are as follows: CNTO136MDD2001 (NCT02473289); 67953964MDD2001 (NCT03559192); 42847922MDD2001 (NCT03227224); 42847922MDD2002 (NCT03321526); 54135419SUI3001 (NCT 03039192);54135419SUI3002(NCT03097133);ESKETINSUI2001(NCT02133001);54135419TRD2005(NCT02918318);ESKETINTRD2003(NCT01998958);ESKETINTRD3001(NCT02417064);and ESKETINTRD3002(NCT02418585). [Figure 38]CRP effect across various clinical trials is shown. High.Diff(PBO-TRT) refers to TE SigPos subjects, Other.Diff(PBO-TRT) refers to TE SigNeg subjects, and High.Diff-Other.Diff(PBO-TRT) refers to signature dominance. ClinicalTrials.gov identifiers for each of the illustrated trials are as follows: CNTO136MDD2001 (NCT02473289); 67953964MDD2001 (NCT03559192); 42847922MDD2001 (NCT03227224); 42847922MDD2002 (NCT03321526); 54135419SUI3001 (NCT 03039192);54135419SUI3002(NCT03097133);ESKETINSUI2001(NCT02133001);54135419TRD2005(NCT02918318);ESKETINTRD2003(NCT01998958);ESKETINTRD3001(NCT02417064);and ESKETINTRD3002(NCT02418585). DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0014] Any individual feature mentioned herein, e.g., a specific embodiment or a specific preferred feature, may be taken alone or in combination with any other feature (including specific embodiments or preferred features) mentioned herein. Thus, a preferred feature may be taken in conjunction with or independently of other preferred features (and also as a specific embodiment).

[0015] The present disclosure is directed to a method comprising administering a therapeutically effective amount of an antidepressant to a patient in need of treatment for depression (e.g., major depressive disorder). For example, a patient with a score of 18 or more as measured by the MADRS or a score of 4 or more on the CGI scale. In some embodiments, the method is for treating treatment-refractory or treatment-resistant depression. In other embodiments, the agent is for treating suicidal ideation. These methods advantageously allow for tailoring an effective regimen to a patient with depression. Such patients include those who have already been diagnosed with MDD, TRD, have suicidal tendencies, or are otherwise untreated for depression. For example, the method is directed to a patient with major depressive disorder accompanied by suicidal ideation or behavior.

[0016] In yet further aspects, the depression comprises major depressive disorder. In certain aspects, the major depressive disorder is major depressive disorder accompanied by suicidal ideation or behavior. In further aspects, the major depressive disorder is treatment-resistant depression.

[0017] In one aspect of the invention, a method of treating depression in a human patient is provided comprising administering to a patient in need thereof an effective amount of an antidepressant, wherein the patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

[0018] Biomarker Signature In certain embodiments, the patient is identified as biomarker signature positive.

[0019] In certain embodiments, the biomarker signature is an inflammatory biomarker signature ("3MM") with a positive status defined by CRP>3mg / L and (TNFα>4pg / mL or sIL6R>25ng / mL). In the disclosed methods using the 3MM biomarker signature, a patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having at least one of: (a) a level of CRP higher than a reference CRP level, and (b) (i) a level of TNF-α higher than a reference TNF-α level, and (ii) a level of sIL6R higher than a reference sIL6R level. In certain embodiments, patients identified as biomarker signature positive exhibit an improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, patients identified as biomarker signature positive exhibit an improvement of about 6.3 MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, patients identified as positive for the biomarker signature are administered an antidepressant and show an improvement in MADRS points compared to a comparison population of patients who are not positive for the biomarker signature. In certain embodiments, patients identified as positive for the biomarker signature are administered an aticaplant or a pharmaceutically acceptable salt thereof and show an improvement in MADRS points compared to a comparison population of patients who are not positive for the biomarker signature. In certain embodiments, patients identified as positive for the biomarker signature are administered an aticaplant or a pharmaceutically acceptable salt thereof and show an improvement of about 4.7 MADRS points compared to a comparison population of patients who are not positive for the biomarker signature. In certain embodiments, patients identified as positive for the biomarker signature are administered an esketamine and show an improvement in MADRS points compared to a comparison population of patients who are not positive for the biomarker signature.

[0020] In certain embodiments, the biomarker signature is an inflammatory biomarker signature ("2MM") with a positive status defined by CRP>3 mg / L and sIL6R>25 ng / mL. In the disclosed methods using the 2MM biomarker signature, a patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of CRP higher than a reference CRP level and a level of sIL6R higher than a reference sIL6R level. In certain embodiments, patients identified as biomarker signature positive show improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, patients identified as biomarker signature positive show improvement in MADRS points compared to a comparison population of patients administered esketamine and not biomarker signature positive.

[0021] In certain embodiments, the biomarker signature is an inflammatory biomarker signature ("CRP") with a positive status defined by CRP>3mg / L. In the disclosed methods using the CRP biomarker signature, a patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of CRP higher than a reference CRP level. In certain embodiments, patients identified as biomarker signature positive show improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, patients identified as biomarker signature positive show improvement in MADRS points compared to a comparison population of patients administered esketamine and not biomarker signature positive.

[0022] In certain embodiments, the biomarker signature is a dynorphin ("DYN") biomarker signature with a positive status identified by DYN>δpg / mL. In the disclosed methods using the dynorphin biomarker signature, a patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of dynorphin higher than a reference dynorphin level. In certain embodiments, a patient identified as biomarker signature positive exhibits an improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, a patient identified as biomarker signature positive exhibits an improvement in MADRS points compared to a comparison population of patients administered an antidepressant and not biomarker signature positive. In certain embodiments, a patient identified as biomarker signature positive exhibits an improvement in MADRS points compared to a comparison population of patients administered aticaprant or a pharmacologic acceptable salt thereof and not biomarker signature positive. In certain embodiments, patients identified as positive for the biomarker signature do not exhibit an improvement in MADRS points at dynorphin levels greater than about 48 pg / mL, hi certain embodiments, patients identified as positive for the biomarker signature exhibit an improvement in MADRS points relative to a comparison population of patients administered esketamine who are not positive for the biomarker signature.

[0023] In certain embodiments, the biomarker signature is a 3MM positive or DYN positive signature. In the disclosed methods using the 3MM or DYN biomarker signature, a patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having (a) a level of CRP higher than a reference CRP level, and at least one of (i) a level of TNF-α higher than a reference TNF-α level, and (ii) a level of sIL6R higher than a reference sIL6R level, or (b) a level of dynorphin higher than a reference dynorphin level. In certain embodiments, a patient identified as biomarker signature positive shows an improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, a patient identified as biomarker signature positive shows an improvement in MADRS points compared to a comparison population of patients administered an antidepressant and not biomarker signature positive. In certain embodiments, patients identified as positive for the biomarker signature are administered aticaplant or a pharma- ceutically acceptable salt thereof and show an improvement in MADRS points compared to a comparison population of patients not positive for the biomarker signature. In certain embodiments, patients identified as positive for the biomarker signature do not show an improvement in MADRS points at dynorphin levels above about 48 pg / mL. In certain embodiments, patients identified as positive for the biomarker signature are administered esketamine and show an improvement in MADRS points compared to a comparison population of patients not positive for the biomarker signature.

[0024] In certain embodiments, the biomarker signature is a 3MM positive and DYN positive signature. In the disclosed methods using the 3MM or DYN biomarker signature, a patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having (a) a level of CRP higher than a reference CRP level, and at least one of (i) a level of TNF-α higher than a reference TNF-α level, and (ii) a level of sIL6R higher than a reference sIL6R level, and (b) a level of dynorphin higher than a reference dynorphin level. In certain embodiments, patients identified as biomarker signature positive show improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, patients identified as biomarker signature positive show improvement in MADRS points compared to a comparison population of patients not biomarker signature positive. In certain embodiments, patients identified as positive for the biomarker signature do not show MADRS point improvement at dynorphin levels greater than about 48 pg / mL.

[0025] In any of the disclosed embodiments, the reference dynorphin level is between about 6.2 pg / mL and about 116.2 pg / mL. In certain embodiments, the reference dynorphin level is between about 6 pg / mL and about 116 pg / mL. In certain embodiments, the reference dynorphin level is between about 11.4 pg / mL and about 116.2 pg / mL. In certain embodiments, the reference dynorphin level is between about 11 pg / mL and about 116 pg / mL. In certain embodiments, the reference dynorphin level is between about 24 pg / mL and about 116 pg / mL. In certain embodiments, the reference dynorphin level is between about 19.9 pg / mL and about 30 pg / mL. In certain embodiments, the reference dynorphin level is between about 20 pg / mL and about 30 pg / mL. In certain embodiments, the reference dynorphin level is between about 6.2 pg / mL and about 19.9 pg / mL. In certain embodiments, the reference dynorphin level is between about 6.2 pg / mL and about 30 pg / mL. In certain embodiments, the reference dynorphin level is about 11.4 pg / mL. In certain embodiments, the reference dynorphin level is about 11 pg / mL. In certain embodiments, the reference dynorphin level is about 19.9 pg / mL. In certain embodiments, the reference dynorphin level is about 20 pg / mL. In certain embodiments, the reference dynorphin level is about 24 pg / mL. In certain embodiments, the reference dynorphin level is about 30 pg / mL. In certain embodiments, the reference dynorphin level is about 50 pg / mL. In certain embodiments, the reference dynorphin level is less than about 48.7 pg / mL. In certain embodiments, the reference dynorphin level is less than about 50 pg / mL.

[0026] In certain embodiments, the biomarker signature is a 4MM positive signature. In the disclosed methods using the 4MM biomarker signature, a patient is identified as biomarker signature positive if a biological sample obtained from the patient has a dynorphin level higher than a first reference dynorphin level, or is identified as having at least one of (i) a CRP level higher than a reference CRP level, and a TNF-α level higher than a reference TNF-α level, and a sIL6R level higher than a reference sIL6R level, and (ii) a dynorphin level higher than a second reference dynorphin level, where both (i) and (ii) are present. In certain embodiments, patients identified as biomarker signature positive show an improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, patients identified as biomarker signature positive show an improvement in MADRS points compared to a comparison population of patients not biomarker signature positive. In certain embodiments, patients identified as positive for the biomarker signature do not show MADRS point improvement at dynorphin levels greater than about 48 pg / mL.

[0027] In any of the disclosed embodiments, the first reference dynorphin level is between about 6.2 pg / mL and about 116.2 pg / mL. In certain embodiments, the first reference dynorphin level is between about 6 pg / mL and about 116 pg / mL. In certain embodiments, the first reference dynorphin level is between about 11.4 pg / mL and about 116.2 pg / mL. In certain embodiments, the first reference dynorphin level is between about 11 pg / mL and about 116 pg / mL. In certain embodiments, the first reference dynorphin level is between about 24 pg / mL and about 116 pg / mL. In certain embodiments, the first reference dynorphin level is between about 19.9 pg / mL and about 30 pg / mL. In certain embodiments, the first reference dynorphin level is between about 20 pg / mL and about 30 pg / mL. In certain embodiments, the first reference dynorphin level is between about 6.2 pg / mL and about 19.9 pg / mL. In certain embodiments, the first reference dynorphin level is between about 6.2 pg / mL and about 30 pg / mL. In certain embodiments, the first reference dynorphin level is about 11.4 pg / mL. In certain embodiments, the first reference dynorphin level is about 11 pg / mL. In certain embodiments, the first reference dynorphin level is about 19.9 pg / mL. In certain embodiments, the first reference dynorphin level is about 20 pg / mL. In certain embodiments, the first reference dynorphin level is about 24 pg / mL. In certain embodiments, the first reference dynorphin level is about 30 pg / mL. In certain embodiments, the first reference dynorphin level is about 50 pg / mL. In certain embodiments, the first reference dynorphin level is less than about 48.7 pg / mL. In certain embodiments, the first reference dynorphin level is less than about 50 pg / mL.

[0028] In any of the disclosed embodiments, the second reference dynorphin level is about 8 pg / mL.

[0029] In certain embodiments, the first reference dynorphin level is about 50 pg / mL and the second reference dynorphin level is about 8 pg / mL. In further embodiments, the first reference dynorphin level is about 24 pg / mL and the second reference dynorphin level is about 8 pg / mL.

[0030] In any one of the disclosed embodiments, a biomarker correlate of any of the biomarkers may be used, for example, a biomarker correlate of CRP, TNF-α, sIL6R, or dynorphin. As used herein, a "biomarker correlate" of a biomarker is another marker whose level or activity correlates with the level or activity of the biomarker. For example, if a biomarker is X and the level of Y correlates with the level of X, then Y is a biomarker correlate of X.

[0031] As used herein, "CRP" refers to C-reactive protein. In certain embodiments, CRP has the UniProtKB / Swiss-Prot number P02741.

[0032] As used herein, "TNF-α" refers to tumor necrosis factor alpha. In certain embodiments, TNF-α has the UniProtKB / Swiss-Prot number P01375.

[0033] As used herein, "IL6R" refers to the interleukin 6 receptor. In certain embodiments, IL6R has the UniProtKB / Swiss-Prot number P08887. As used herein, "sIL6R" refers to the soluble form of IL6R.

[0034] As used herein, "DYN" refers to dynorphin. In certain embodiments, CYN has the UniProtKB / Swiss-Prot number P01213.

[0035] In any of the disclosed embodiments, the reference CRP level is about 3 mg / L.

[0036] In any of the disclosed embodiments, the reference TNF-α level is about 4 pg / mL.

[0037] In any of the disclosed embodiments, the reference sIL6R level is about 25 ng / mL.

[0038] In any of the disclosed embodiments, reference CRP, TNF-α, sIL6R and / or dynorphin reference levels may be calculated according to the methods disclosed in the Examples.

[0039] Specific Terms Some of the quantitative expressions given herein are not modified by the term "about". Regardless of whether the term "about" is explicitly used or not, it is understood that all quantities given herein are meant to refer to the actual given value, and also to the approximation of such given value that is reasonably estimated based on ordinary skill in the art, including the approximation of such given value by experimental and / or measurement conditions.

[0040] As used herein, unless otherwise specified, the terms "subject" and "patient" refer to a human being who has been the object of treatment, observation or experiment. Preferably, the patient is experiencing and / or exhibiting at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the patient is an adult. As used herein, "adult" refers to a human who is about 18 years of age or older. In certain aspects, the patient is 65 years of age or older, i.e., elderly.

[0041] In some embodiments, the subject or patient is an adult. As used herein, the term "adult" as used herein refers to a human who is between about 18 and about 65 years of age.

[0042] In other embodiments, the subject or patient is aged or elderly. As used herein, the terms "aged" and "elderly" are used interchangeably to refer to a human subject aged about 65 years or older. Elderly patients aged ≧65 to ≦75 years are likely to respond better to treatment than patients aged ≧75 years.

[0043] In a further embodiment, the subject or patient is a pediatric subject. As used herein, the term "pediatric" refers to a human subject younger than about 18 years of age.

[0044] As used herein, unless otherwise indicated, the terms "treat", "treatment" and the like are intended to include the management and care of a subject or patient (preferably a mammal, more preferably a human) for the purpose of combating a disease, condition, or disorder and also include the administration of a compound described herein to prevent the occurrence of symptoms or complications, alleviate one or more symptoms or complications, or eliminate the disease, condition, or disorder.

[0045] As used herein, the term "depression" (also referred to as depressive disorder) includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholia, midlife depression, late life depression, bipolar depression, depression due to an identifiable stressor, treatment-resistant depression, or combinations thereof. In certain embodiments, the depression is major depressive disorder. In other embodiments, the major depressive disorder is accompanied by depressive features or anxiety distress. In further embodiments, the depression is treatment-resistant depression. In other embodiments, the depression is major depressive disorder accompanied by suicidal ideation.

[0046] As is known in the art, a patient is considered to have major depressive disorder if they exhibit five or more symptoms during the same two-week period that are a change from previous functioning, and depressed mood and / or loss of interest / pleasure must be present, excluding symptoms clearly attributable to another physical illness. See, e.g., Table A.

[0047] [Table 1]

[0048] In some embodiments, the following criteria are also met to be diagnosed with MDD:

[0049] [Table 2]

[0050] Major depressive disorder may be classified as mild, moderate, or severe. In some embodiments, MDD is mild. In other embodiments, MDD is moderate. In further embodiments, MDD is severe. As used herein, "mild MDD" applies to patients who have few, if any, symptoms beyond those required to make a diagnosis, the intensity of symptoms is distressing but manageable, and the symptoms result in mild impairment in social or occupational functioning. Mild MDD may be a single episode (ICD-10F32.0) or recurrent episodes (ICD-10F33.0). "Moderate MDD" applies to patients who have a number of symptoms, intensity of symptoms, and / or functional impairment that is between those designated as "mild" and those designated as "severe." Moderate MDD may be a single episode (ICD-10F32.1) or recurrent episodes (ICD-10F33.1). "Severe MDD" refers to patients in whom the number of symptoms significantly exceeds that required to make a diagnosis, the intensity of symptoms is severely distressing, the symptoms significantly interfere with social and occupational functioning, and emergency symptom management is required. In some embodiments, severe MDD can be single episode (ICD-10F32.2) or recurrent episodes (ICD-10F33.2). In other embodiments, MDD is classified according to the DSM-5 definition in Table B.

[0051] [Table 3]

[0052] Several scales are known in the art that can be used to diagnose or monitor patients with MDD. Examples of these scales include, but are not limited to, the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression-Severity (CGI-S) scale, the Symptoms of Major Depressive Disorder Scale (SMDDS), the Self-Assessment of Treatment Experience (SATE) scale, and the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), or MGH-ATRQ.

[0053] In some embodiments, the MADRS is utilized to diagnose and / or monitor patients. The MADRS is a 10-item rating scale used in antidepressant drug trials. It is administered by clinicians and designed to be used in subjects with MDD to measure the overall severity of depressive symptoms. The MADRS scale is validated, reliable, and accepted by regulatory health agencies as the primary scale for determining efficacy in major depression. In some embodiments, the MADRS is administered using the Structured Interview Guide for MADRS (SIGMA). The scale consists of 10 items, each scored from 0 (absent or normal item) to 6 (severe or continued presence of symptoms), with a maximum total score of 60. Higher scores indicate a more severe condition. The MADRS assesses apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, fatigue, apathy (attention level), pessimistic thoughts, and thoughts of suicide.

[0054] In another embodiment, the CGI-S is utilized to diagnose and / or monitor depression in patients. The CGI-S is a scale that evaluates the severity of a subject's illness at the time of evaluation, compared to the clinician's past experience with subjects with the same diagnosis and improvement with treatment. The CGI-S provides an overall clinician-determined summary scale of the severity of the subject's illness, taking into account all available information, including the subject's medical history, psychosocial situation, symptoms, behavior, and the impact of symptoms on the subject's ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 0 to 7. Taking into account the entire clinical experience, subjects are rated for the severity of their mental illness at the time of evaluation according to the following: 0=not rated, 1=normal (not sick at all), 2=borderline psychotic, 3=mildly sick, 4=moderately sick, 5=significantly sick, 6=severely sick, 7=most severely ill patient.

[0055] In a further embodiment, the SMDDS is utilized to diagnose and / or monitor depression in a patient. The SMDDS is a subjective assessment of the patient. The SMDDS is a 16-item PRO scale. Each item is rated by the subject according to a 5-point Likert scale. The subject answers each question using a rating scale between 0 ("never" or "never") and 4 ("extremely" or "always"). The total score ranges from 0 to 60. The SMDDS uses a 7-day recall period and a verbal rating scale. Higher scores indicate more severe depressive symptomatology.

[0056] In yet another embodiment, the SATE is utilized to diagnose and / or monitor depression in patients. The SATE is a 1-3 time questionnaire administered to subjects away from clinical settings such as at home, i.e. when they are unable to complete other assessments. The SATE is useful for assessing improvement or worsening of a subject's depressive symptoms over a short period of time. To assess overall depression, subjects select one of the following options: improved, unchanged, or worsened; for improvement of depression, subjects select one of the following options: slightly improved, much improved, very much improved; for worsening of depression, subjects select slightly worse, much worse, very much worse. See Table C.

[0057] [Table 4]

[0058] The MGH-ATRQ is a self-assessment scale used to determine treatment resistance in patients with MDD. This questionnaire examines antidepressant therapy history, using specific anchor points to define the appropriateness of both the dose and duration of each antidepressant trial, as well as the degree of symptom improvement. The MGH-ATRQ allows for the determination of treatment resistance in depression and is known to those skilled in the art.

[0059] As used herein, the term "non-responder" refers to a patient who does not fully recover on an antidepressant (eg, 25% or less change from baseline in total MADRS score).

[0060] As used herein, the term "episode of major depressive disorder" refers to a condition in which a patient experiences a major depressive disorder episode that is more severe than the symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. th Major depressive disorder refers to a continuous period (e.g., about 2 or 3 weeks or more) during which a person has sufficient symptoms of major depressive disorder to meet the criteria for major depression as defined in the DSM-5 (DSM-5 Edition).

[0061] As used herein, "suicide" is "the act of taking one's own life." See http: / / en.wikipedia.org / wiki / Suicide-cite_note-7. Suicide includes suicide attempts or non-fatal suicidal behavior, which is self-injury involving a desire to end one's life and does not result in death. A suicide attempt is a self-initiated sequence of actions by an individual who, at the time of initiation, expects that the series of actions will lead to their own death.

[0062] As used herein, "suicidal ideation" refers to thoughts about or abnormal obsession with suicide, or thoughts of wanting to end one's life or not wanting to live any longer, but not necessarily making any active attempt to do so. Suicidal ideation ranges from transient to chronic and progression to detailed planning, role-playing, and failed attempts, which may be deliberately constructed to fail or be discovered, or may be fully intended to result in death. In some embodiments, a patient is classified as "suicidal" when the patient has an average baseline MADRS total score of about 38 or greater. In other embodiments, a patient is classified as suicidal when the patient has an average baseline BBSS score of 22 or greater. In further embodiments, a patient is classified as suicidal when the patient has a score of 6 or greater on the SIBAT Clinical Global Assessment of Suicide Risk. In still other embodiments, a patient has a combination of one or more of these scores.

[0063] As used herein, the terms "concomitant therapy," "combination therapy," "adjunctive therapy," "adjunctive therapy," "combination treatment," and "concomitant administration" are intended to mean treatment of a patient in need thereof by administering esketamine in combination with one or more antidepressants, wherein the esketamine and antidepressants are administered by any suitable means. In some embodiments, esketamine is administered in a regimen with one to five antidepressants. In other embodiments, esketamine is administered in a regimen with one, two, three, four, or five antidepressants. In other embodiments, esketamine is administered in a regimen with one or two antidepressants. In further embodiments, esketamine is administered in a regimen with an antidepressant currently administered to the patient. In other embodiments, esketamine is administered in a regimen with a different antidepressant. In still further embodiments, esketamine is administered in a regimen with an antidepressant not previously administered to the patient. In still other embodiments, esketamine is administered in a regimen with an antidepressant previously administered to the patient. When esketamine and antidepressant are administered in separate dosage forms, the number of doses administered per day for each compound may be the same or different, and more typically, different.The antidepressant may be administered as prescribed by the attending physician and / or by its label, and esketamine is administered as described herein.Typically, the patient is under concurrent treatment with both an antidepressant and esketamine, both of which are administered according to their prescribed dosing regimen.

[0064] As used herein, unless otherwise specified, the term "antidepressant" refers to any pharmaceutical agent that can be used to treat depression. Suitable examples include, but are not limited to, monoamine oxidase inhibitors (MAOIs), tricyclic serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic and specific serotonergic agents, or atypical antipsychotics. Other examples include monoamine oxidase inhibitors such as irreversible MAOIs (phenelzine, tranylcypromine) and reversible MAOIs (moclobemide); tricyclic antidepressants such as imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, and amoxapine; tetracyclic antidepressants such as maprotiline; acyclics such as nomifensine; triazolopyridines such as trazodone; serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine; serotonin receptor antagonists such as nefazadone and tianeptine; venlafaxine, milnacipran, desvenlafaxine, and desvenlafaxine. These include, but are not limited to, serotonin noradrenergic reuptake inhibitors such as duloxetine and levomilnacipran; noradrenergic and specific serotonergic agents such as mirtazapine; noradrenaline reuptake inhibitors such as reboxetine and edivoxetine; anticholinergic drugs, e.g., scopolamine; lithium; triple reuptake inhibitors; atypical antipsychotics such as bupropion; natural products such as kava and hypericum perforatum; dietary supplements such as s-adenosylmethionine; and neuropeptides such as thyrotropin releasing hormone; compounds targeting neuropeptide receptors such as neurokinin receptor antagonists; and hormones such as triiodothyronine.In some embodiments, the antidepressant is imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, kavakava, hypericum perforatum, s-adenosylmethionine, thyroid hormone releasing hormone, neurokinin receptor antagonist, or triiodothyronine. Preferably, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine, and sertraline. Preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic-specific serotonergic drugs, atypical antipsychotics, and / or adjunctive therapy with antipsychotics (e.g., risperidone, olanzapine, quetiapine, aripiprazole, and ziprapradone). More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors. In other embodiments, the antidepressant is phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine, bupropion, thyrotropin-releasing hormone, and triiodothyronine.In further embodiments, the antidepressant is administered in combination with one or more compounds selected from the group consisting of lithium, riluzole, phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, levomilnacipran, mirtazapine, and bupropion. More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, and fluvoxamine. More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine.

[0065] Therapeutically effective amounts / dosage levels and dosing regimens of antidepressants (e.g., monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic-specific serotonergic agents, noradrenaline reuptake inhibitors, natural products, dietary supplements, neuropeptides, compounds targeting neuropeptide receptors, hormones, and other pharmaceutical agents described herein) may be readily determined by one of skill in the art. For example, therapeutic dosages and regimens for pharmaceutical agents approved for sale are generally available and are listed, for example, on package labels, standard dosing guidelines, standard dosing references such as the Physician's Desk Reference (Medical Economics Company or online at http: / / / www.pdrel.com), or other sources.

[0066] As used herein, the term "antipsychotic" includes, but is not limited to: (a) typical or conventional antipsychotics, such as phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin), thioxanthenes (e.g., thiothixene, flupentixol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), substituted benzamides (e.g., sulpride, amisulpride), and the like; (b) Atypical antipsychotics and mood stabilizers, such as paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, ORG-5222 (Organon), and others, such as sonepiprazole, aripiprazole, nemonapride, SR-31742 (Sanofi), CX-516 (Cortex), SC-111 (Scotia), NE-100 (Taisho), divalproate (mood stabilizer), and the like.

[0067] In one embodiment, the "atypical antipsychotic" is selected from the group consisting of aripiprazole, quetiapine, olanzapine, risperidone, and paliperidone. In another embodiment, the atypical antipsychotic is selected from the group consisting of aripiprazole, quetiapine, olanzapine, brexipirazole, lurasidone, and risperidone, preferably, the atypical antipsychotic is selected from the group consisting of aripiprazole, quetiapine, and olanzapine.

[0068] As used herein, the term "treatment-refractory or treatment-resistant depression" and the abbreviation "TRD" are intended to be defined as major depressive disorder in patients who have not responded adequately to at least two different antidepressants, preferably 2-5 antidepressants, during their current depressive episode. In another embodiment, TRD is defined as major depressive disorder in patients who have not responded adequately to at least two oral antidepressants of adequate dose and duration during their current depressive episode.

[0069] In other embodiments, the methods for the treatment of depression can be combined with adjunctive therapies, such as antipsychotic therapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or combinations thereof.

[0070] Those skilled in the art will recognize that non-response to a given set of suitable antidepressants can be determined retrospectively or prospectively. In one embodiment, at least one of the non-response to the suitable set of antidepressants is determined prospectively. In another embodiment, at least two of the non-response to the suitable set of antidepressants is determined prospectively. In another embodiment, at least one of the non-response to the suitable set of antidepressants is determined retrospectively. In another embodiment, at least two of the non-response to the suitable set of antidepressants is determined retrospectively in the current depressive episode.

[0071] The "at least two oral antidepressants" or "at least two different oral depressants" are administered to the patient at appropriate dosages, which may be determined by the attending physician. Similarly, the antidepressants are administered for a suitable duration, which may be determined by the attending physician.

[0072] As used herein, the term "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue system, animal or human, including alleviation of symptoms of the disease or disorder being treated, as desired by a researcher, veterinarian, physician or other clinician. In some embodiments, antidepressants are utilized in a therapeutically effective amount as determined by the attending physician. In other embodiments, esketamine is utilized in a therapeutically effective amount. In other embodiments, aticaplant or a pharmaceutically acceptable salt thereof is utilized in a therapeutically effective amount.

[0073] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from combining the specified ingredients in the specified amounts.

[0074] As used herein, "stable remission" refers to a patient having a MADRS total score of 12 or less for at least three of the last four weeks after the patient achieves a substantially complete response to esketamine during the induction phase. In certain exemplified embodiments herein, patients in "stable remission" include patients with one deviation in MADRS total score of greater than 12 or one missed MADRS assessment at week 13 or 14 following the induction phase. In other embodiments, patients in "stable remission" include patients with a MADRS total score of 12 or less at weeks 15 and 16 following the induction phase.

[0075] As used herein, "stable response" refers to a patient's MADRS total score decreasing by 50% or more from baseline (Run-in Day 1; pre-randomization / pre-first nasal dose) in each of the final 2 weeks, whereafter the patient has demonstrated a substantially complete response to esketamine during the run-in phase but does not meet the criteria for stable remission.

[0076] Methods and uses involving Atika Plant In one aspect of the invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient is identified as having either (a) anhedonia or (b) a biomarker signature positive, where the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level, if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. In a further aspect of the present invention, there is provided a method of treating major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient is identified as having (a) anhedonia, or (b) a biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level, and the patient has an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0077] In a further aspect of the present invention, there is provided a method of treating major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient is identified as having (a) anhedonia, and (b) a biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. In a further aspect of the present invention, there is provided a method of treating major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient (a) has anhedonia, and (b) is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level, and the patient has an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0078] In a further aspect of the present invention, there is provided a method of treating major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient (a) has anhedonia or (b) is biomarker signature positive, where the patient is biomarker signature positive if a biological sample obtained from the patient exhibits a level of at least one biomarker that is higher or lower than a reference biomarker level. In a further aspect of the present invention, there is provided a method of treating major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient (a) has anhedonia or (b) is biomarker signature positive when a biological sample obtained from the patient exhibits a level of at least one biomarker that is higher or lower than a reference biomarker level, and the patient has an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0079] Further described herein is aticaplant or a pharma- ceutically acceptable salt thereof for use in the treatment of major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient is identified as having (a) anhedonia, or (b) a biomarker signature positive, when a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. Further described herein is aticaplant or a pharma- tically acceptable salt thereof for use in the treatment of major depressive disorder (MDD) in a human patient, comprising, consisting of, or consisting essentially of administering to a patient in need thereof an effective amount of aticaplant or a pharma- tically acceptable salt thereof, wherein the patient is identified as having (a) anhedonia, or (b) a biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level, and the patient has an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0080] In another aspect of the present invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising administering an effective amount of aticaplant or a pharmaceutically acceptable salt thereof to a patient in need thereof, the patient being identified as a biomarker signature positive, the patient being identified as a biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. In another aspect of the present invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising administering an effective amount of aticaplant or a pharmaceutically acceptable salt thereof to a patient in need thereof, the patient being identified as a biomarker signature positive, the patient being identified as a biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level, the patient having an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0081] In another aspect of the present invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising administering an effective amount of aticaplant or a pharmaceutically acceptable salt thereof to a patient in need thereof, the patient being biomarker signature positive, the patient being biomarker signature positive if a biological sample obtained from the patient exhibits a level of at least one biomarker that is higher or lower than a reference biomarker level. In another aspect of the present invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising administering an effective amount of aticaplant or a pharmaceutically acceptable salt thereof to a patient in need thereof, the patient being biomarker signature positive, the patient being biomarker signature positive if a biological sample obtained from the patient exhibits a level of at least one biomarker that is higher or lower than a reference biomarker level, the patient having an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0082] In a further aspect of the present invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising, consisting of, or consisting essentially of: evaluating a biological sample obtained from the patient for the presence of a level of at least one biomarker that is higher or lower than a reference biomarker level; and administering to the patient an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof. In a further aspect of the present invention, a method of treating major depressive disorder (MDD) in a human patient is provided, comprising, consisting of, or consisting essentially of: evaluating a biological sample obtained from the patient for the presence of a level of at least one biomarker that is higher or lower than a reference biomarker level; and administering to the patient an effective amount of aticaplant or a pharma-ceutically acceptable salt thereof, wherein the patient has an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0083] Further described herein is aticaplant or a pharma- ceutically acceptable salt thereof for use in treating major depressive disorder (MDD) in a human patient, comprising administering to a patient in need thereof an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof, wherein the patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. Further described herein is aticaplant or a pharma- tically acceptable salt thereof for use in the treatment of major depressive disorder (MDD) in a human patient, comprising administering an effective amount of aticaplant or a pharma- tically acceptable salt thereof to a patient in need thereof, wherein the patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level, and wherein the patient has an inadequate response to selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) treatment, or a combination thereof.

[0084] In any of the embodiments of the above-mentioned method of treatment, the patient had an inadequate response to other antidepressant therapy prior to treatment with Aticaplant or a pharma- ceutically acceptable salt thereof. In certain embodiments, the other antidepressant therapy included one or more antidepressants. In certain embodiments, the one or more antidepressants included a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI) therapy, or a combination thereof. In certain embodiments, the one or more antidepressants included a selective serotonin reuptake inhibitor (SSRI). In certain embodiments, the one or more antidepressants included a serotonin-norepinephrine reuptake inhibitor (SNRI) therapy. In certain embodiments, the one or more antidepressants included a selective serotonin reuptake inhibitor (SSRI) and a serotonin-norepinephrine reuptake inhibitor (SNRI) therapy.

[0085] In certain embodiments, described herein are methods for identifying a patient as a candidate for treatment with Aticaplant or a pharma- ceutically acceptable salt thereof if the patient is biomarker signature positive, where the patient is identified as being biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. In certain embodiments, the method further comprises administering to the patient an effective amount of Aticaplant or a pharma-ceutically acceptable salt thereof.

[0086] It will be understood that for each of the methods of treatment described herein, the method of treatment may also be configured as a method of manufacturing a medicament for the treatment of the described indication, or as an aticaplant for use in the treatment of the described indication.

[0087] Because MDD alone is difficult to treat, patients with anhedonia are even more problematic because their ability to measure pleasure is impaired.Therefore, such patients often receive inadequate treatment due to, among other things, ineffective medication, repeated unnecessary medical appointments, lack of patient compliance, and overall patient frustration.In addition, antidepressants are known to have various side effects, such as weight gain, metabolic side effects, extrapyramidal symptoms, akathisia, cognitive impairment, among other things.Therefore, patients may choose to refrain from or discontinue taking antidepressants to avoid or prevent any side effects.

[0088] The methods described herein are effective in managing depression and anhedonia in patients using Atikaplant. Desirably, the methods allow patients to successfully manage their depression and simultaneously reduce anhedonia. In certain embodiments, patients treated according to the methods described have high anhedonia as measured by a total score of ≧32 on the Snaith-Hamilton Pleasure Scale (SHAPS). The term "anhedonia" as used herein refers to a lack or reduced ability to experience pleasure in daily activities. The term anhedonia includes loss of pleasure in sensory experiences (i.e., touch, taste, smell), as well as social interactions. In some embodiments, anhedonia and depressed mood are diagnostic criteria for a major depressive episode as part of MDD. Anhedonia also describes a deficit in one or more components (e.g., desire, liking, and learning) of reward-related behavior, also known as the pleasure cycle. The pleasure cycle can be divided into three stages: the appetitive stage (governed by desire), the consummatory stage (governed by preferences), and the satisficing stage (governed by learning). The appetitive stage is characterized by an initial expenditure of energy to obtain a reward. The consummatory stage is the enjoyment of the reward, and the satisficing stage is characterized by learning and feedback integration.

[0089] To assess potential effects on anhedonia, an anhedonia scale can be used. For example, the Snaith-Hamilton Analysis of Pleasure Scale (SHAPS) is a validated scale for the measurement of anhedonia. The SHAPS is a subject completion scale in which subjects score whether they experience pleasure when performing a list of activities or experiences. The SHAPS is a self-report 14-item set developed for the assessment of hedonic capacity. Subjects score whether they experience pleasure when performing a list of activities or experiences. Subjects can rate their responses as 1-4, where 1 indicates "definitely agree," 2 indicates "agree," 3 indicates "disagree," and 4 indicates "definitely disagree." The subject's item responses are summed to obtain a total score ranging from 14-56. A higher total SHAPS score indicates a higher level of current anhedonia. Physician / clinical judgment can be used to assess anhedonia separately or in conjunction with the anhedonia scale.

[0090] In some embodiments, the patient has anhedonia. In some embodiments, the patient has moderate anhedonia. In other embodiments, the patient has severe anhedonia. The assessment of moderate or severe anhedonia is typically determined by physician / clinical judgment and / or one or more tests that provide insight into whether the patient has anhedonia. For example, the severity of anhedonia can be determined using the SHAPS method. In some embodiments, patients with moderate or severe anhedonia are considered to have high levels of anhedonia. For example, patients with a SHAPS score of 38 or higher are considered to have moderate to severe anhedonia, which can be considered to have high levels of anhedonia. In some embodiments, high levels of anhedonia reflect a SHAPS score of at least about 40, about 42, about 44, about 46, about 48, about 50, about 52, about 54, about 56, about 58, or more. Patients with mild or anhedonia are considered to have low levels of anhedonia as assessed by physician / clinical judgment and / or one or more tests. For example, patients with a SHAPS score of less than 38 are considered to have low anhedonia. In certain embodiments, patients with mild anhedonia are considered to have a SHAPS score of less than 20 to 38, e.g., 20 to about 36, about 22 to about 36, about 24 to about 36, about 26 to about 36, about 26 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 36, about 28 to about 36, about 30 to about 36, about 32 to about 36, about 34 to about 3 36, about 20 to about 34, about 22 to about 34, about 24 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 36, about 28 to about 34, about 28 to about 32, about 28 to about 30, about 30 to about 36, about 30 to about 34, about 30 to about 32, about 32 to about 36, about 32 to about 34, or about 34 to about 36. Typically, a SHAPS score of less than 20 can be considered to correspond to normal hedonic function and, for purposes of the present disclosure, would be classified in the low category of anhedonia, e.g., a SHAPS score of less than 38.

[0091] In some embodiments, the patient's anhedonia is reduced from a high level of anhedonia to a low level of anhedonia. In yet other embodiments, the patient's anhedonia is reduced by at least about 40% as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atikaplant. In yet other embodiments, the patient's anhedonia is reduced by at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atikaplant. In yet further embodiments, in still other embodiments, the patient's anhedonia is reduced by about 40 to about 90%, about 50 to about 90%, about 60 to about 90%, about 70 to about 90%, about 80 to about 90%, about 40 to about 80%, about 50 to about 80%, about 60 to about 80%, about 70 to about 80%, about 40 to about 70%, about 50 to about 70%, about 60 to about 70%, about 40 to about 60%, about 50 to about 60%, or about 50 to about 60% as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atika Plant. In other embodiments, the patient's anhedonia is improved, i.e., reduced by 100%, as measured by the change from baseline in the total score on the Anhedonia Scale after treatment with Atika Plant.

[0092] The reduction in anhedonia after starting treatment with Atika Plant can be measured relative to the patient's anhedonia measured before treatment with Atika Plant, i.e., baseline anhedonia measurement. In this way, the treating clinician can calculate the change in anhedonia from baseline to real-time anhedonia measurement at any time after treatment with Atika Plant. Thus, a standard method for measuring anhedonia can be used, such as an anhedonia scale, e.g., SHAPS.

[0093] Desirably, the baseline anhedonia measurements are obtained within about one week of initiating treatment with Atikaplant. In some embodiments, the baseline anhedonia measurements are obtained about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day prior to initiating treatment with Atikaplant. In further embodiments, the baseline anhedonia measurements are obtained about 24 hours, about 18 hours, about 12 hours, about 8 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, or about 15 minutes prior to initiating treatment with Atikaplant.

[0094] The change in the patient's anhedonia depends on several factors, including, but not limited to, the severity of the anhedonia, the patient's sensitivity to the Atika plant, and other medications being administered, among others. In some embodiments, the patient's anhedonia is reduced about 3 weeks after Atika plant treatment. In other embodiments, the patient's anhedonia is reduced about 3 weeks after Atika plant treatment. In further embodiments, the patient's anhedonia is reduced about 3 to about 6 weeks after Atika plant treatment, and in certain embodiments by the 6th week. In certain embodiments, the patient's anhedonia is reduced by at least about 40% after about 6 weeks of Atika plant treatment, as measured by the change from baseline in the total score on the Anhedonia Scale. In further embodiments, the patient's anhedonia is reduced within about 3 weeks, and in some embodiments, within about 3 to about 6 weeks, as measured by the change from baseline in the total score on the Anhedonia Scale and / or by physician / clinical judgment.

[0095] The methods described herein have been found to not only improve patients' depression and anhedonia symptoms, but also result in fewer antidepressant side effects, thereby resulting in, among other things, reduced absenteeism (i.e., more doctor visits or interactions), improved cognitive function, improved health-related quality of life, increased interest and engagement in daily activities, improved family and interpersonal relationships, ability to function at work, and reduced hospitalizations.

[0096] In certain embodiments, the patient has had an inadequate response to other antidepressant therapies (i.e., antidepressant medications or treatments used to treat depression other than Aticaplant). As used herein, "inadequate response" refers to a patient experiencing less than about 50% reduction in the severity of depressive symptoms from the start of treatment. Typically, an inadequate response is one in which depression is in a current / active episode. In some embodiments, an inadequate response refers to a patient experiencing less than about 26 to about 50% reduction in the severity of depressive symptoms from the start of treatment. In other embodiments, an inadequate response refers to a patient experiencing a reduction in severity of depressive symptoms of about 26 to about 49, about 26 to about 45, about 26 to about 40, about 26 to about 35, about 26 to about 30, about 30 to about 49, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 49, about 35 to about 45, about 35 to about 40, about 40 to about 49, or about 40 to about 45% from the start of treatment. Patient response may be measured by one or more scales described herein and / or by physician / clinical judgment. In some embodiments, an inadequate response is measured by the MGH-ATRQ, MADRS, or SHAPs. In further embodiments, an inadequate response is measured by the MGH-ATRQ.

[0097] To the extent that a patient is said to have a partial response to treatment, this refers to some mild to moderate improvement in symptoms since the beginning of treatment, but some of the initial symptoms are still present and bothersome to the patient, and the persistence of these symptoms still affects behavior and functioning: for example, the patient's motivation, productivity, and interest in his or her usual activities may still be impaired.

[0098] Antidepressant therapy refers to any medicine that can be used to treat depression. Suitable examples include, but are not limited to, monoamine oxidase inhibitors, tricyclics, tetracyclics, non-cyclic compounds, triazolopyridines, selective serotonin reuptake inhibitors (SSRIs), serotonin receptor antagonists, serotonin noradrenaline reuptake inhibitors (SNRIs), noradrenaline and specific serotonin agonists, noradrenaline reuptake inhibitors, or antipsychotics (typical or atypical antipsychotics). Examples of monoamine oxidase inhibitors include phenelzine, tranylcypromine, moclobemide, etc. Examples of tricyclic antidepressants include imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, etc. Examples of tetracyclics include maprotiline, etc. Examples of acyclic drugs include nomifensine. Examples of triazolopyridines include trazodone. Examples of SSRIs include fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine. Examples of serotonin receptor antagonists include nefazadone. Examples of SNRIs include venlafaxine, milnacipran, desvenlafaxine, duloxetine, and levomilnacipran. Examples of noradrenergic and specific serotonin agonists include mirtazapine. Examples of noradrenaline reuptake inhibitors include reboxetine and edivoxetine. Exemplary antipsychotic drugs include phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin), thioxanthenes (e.g., thiothixene, flupentixol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), substituted benzamides (e.g., sulpride, amisulpride), and the like.Examples of atypical antipsychotics include paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, ORG-5222, sonepiprazole, aripiprazole, nemonapride, SR-31742, CX-516, SC-111, NE-100, divalproate (mood stabilizer), and the like. In further embodiments, the antidepressant therapy includes natural products such as kava-kava, St. John's wort, or dietary supplements such as s-adenosylmethionine. In yet other embodiments, the antidepressant therapy includes a neuropeptide such as thyrotropin releasing hormone, or a compound that targets a neuropeptide receptor, such as a neurokinin receptor antagonist. In yet further embodiments, the antidepressant therapy is a hormone such as triiodothyronine. In other embodiments, the antidepressant therapy is an SSRI, SNRI, or a combination thereof. Preferably, the antidepressant is an SSRI, which is escitalopram, sertraline, paroxetine, fluoxetine, or citalopram. In other embodiments, the antidepressant is an SNRI, which is venlafaxine, duloxetine, vortioxeine, or desvenlafaxine. There are also non-pharmacological treatments, such as psychotherapy and transcranial magnetic stimulation, which are also available and are adjunctive therapeutic options.

[0099] Therapeutically effective amounts / dosage levels for other antidepressant therapies can be readily determined by one of ordinary skill in the art. For example, therapeutic dosages and regimens for pharmaceuticals approved for marketing are generally available and are listed, for example, in package labels, standard dosing guidelines, standard dosing references such as the Physician's Desk Reference (Medical Economics Company or online at http: / / / www.pdrel.com), or other sources.

[0100] In some embodiments, the other antidepressant therapy may include one antidepressant drug. In other embodiments, the other antidepressant therapy includes two or more antidepressants. In further embodiments, the other antidepressant therapy includes two antidepressants. In yet other embodiments, the other antidepressant therapy includes three antidepressants. The attending physician may select the appropriate antidepressant therapy for use as described herein.

[0101] In certain embodiments, the patient has been treated with other antidepressant therapy prior to receiving Atikaplant. In some embodiments, the patient has been treated with other antidepressant therapy, including an SSRI, an SNRI, or a combination thereof. In other embodiments, the patient has stopped other antidepressant therapy prior to initiating treatment with Atikaplant.

[0102] The methods described herein also include adjunctive treatment with a therapeutically effective amount of one or more antidepressants. As used herein, the terms "adjunctive treatment" and "adjunctive therapy" refer to the treatment of a patient in need thereof by administering Aticaplant in combination with one or more antidepressants, where Aticaplant and the antidepressants are administered by any suitable means, simultaneously, sequentially, separately, or in a single pharmaceutical formulation.

[0103] In some aspects, Atikaplant is administered adjunctively with other antidepressants currently administered to the patient, including current antidepressants to which the patient has had an inadequate response. In other embodiments, Atikaplant is administered adjunctively with antidepressants not previously administered to the patient. In yet other embodiments, Atikaplant is administered in a regimen with an antidepressant previously administered to the patient.

[0104] When acicaplant and other antidepressants are administered in separate dosage forms, the number of doses administered per day for each active compound may be the same or different, and more typically, different.Antidepressants may be administered as prescribed by the attending physician and / or by its label, and acicaplant is administered as described herein.Typically, patients are under concurrent treatment with both antidepressants and acicaplant, both of which are administered according to their prescribed dosing regimen.Aticaplant and antidepressants may be administered simultaneously in divided or single forms, at the same or different times during the course of therapy, according to simultaneous or alternating regimens.

[0105] Aticaplant and antidepressant can be administered via the same or different administration routes.Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intranasal (in), intramuscular (im), subcutaneous (sc), transdermal, buccal, or rectal.In some embodiments, Aticaplant is administered orally.

[0106] Treatment with Atikaplant as described herein has several advantages over treatments in the art. In some embodiments, patients do not experience many of the side effects associated with other antidepressants (i.e., antidepressants other than Atikaplant). In certain aspects, patients do not experience weight gain during treatment with Atikaplant. As used herein, the term "weight gain" refers to an increase in a patient's weight compared to the subject's weight prior to taking Atikaplant or the patient's weight assessed at the time of the first administration of Atikaplant. In certain embodiments, patients can actually see a decrease in overall weight compared to the patient's weight prior to receiving Atikaplant. In further embodiments, the patient's weight is stable, i.e., it neither increases nor decreases. In certain embodiments, patients do not experience clinically relevant weight gain, characterized as a weight gain of ≧7%.

[0107] This is in contrast to many other antidepressants for which weight gain, including clinically relevant weight gain, is a common but unfortunate side effect.

[0108] In certain embodiments, administration of acanthopanthracene results in a maximum plasma concentration (C) of acanthopanthracene of about 20 to about 45 ng / mL. max In a further embodiment, administration of acicaplant achieves a maximum plasma concentration (C) of about 25 to about 35 ng / mL of acicaplant. max In yet further embodiments, administration of acicaplant achieves a maximum plasma concentration (C) of about 30 to about 35 ng / mL of acicaplant. max ) to be achieved.

[0109] In a further aspect, the patient does not experience a decrease in sexual function during treatment with Atikaplant. As used herein, the term "decrease in sexual function" refers to a decrease or reduction in one or more components of human sexual activity (i.e., sexual function). In some embodiments, sexual function includes one or more of sexual drive, sexual arousal, vaginal lubrication, erection, orgasmic achievement, or orgasmic satisfaction. In other embodiments, sexual function includes sexual drive. In further embodiments, sexual function includes vaginal lubrication satisfaction. In further embodiments, sexual function includes orgasmic achievement. In yet other embodiments, sexual function includes orgasmic satisfaction. Desirably, the patient's sexual function is assessed upon the first administration of Atikaplant. Thus, the subject's sexual function during Atikaplant intake can be compared to the subject's sexual function prior to Atikaplant administration. Sexual function can be assessed by using standard scales and techniques, such as the Arizona Sexual Experience Scale (ASEX). The ASEX is used to investigate whether Atikaplant has an additional positive or negative effect on sexual function. The ASEX is a five-item rating scale administered to patients that quantifies sexual drive, sexual arousal, vaginal lubrication or erection, ability to achieve orgasm, and satisfaction. Scores range from 5 to 30, and two different versions of the scale (male and female) are available.

[0110] Other scales can be utilized to determine the effectiveness of the methods used herein to treat patients. Examples include the Cognitive and Physical Function Questionnaire (CPFQ), the Karolinska Sleepiness Scale (KSS), and the Temporal Pleasure Experience Scale (TEPS). The CPFQ is a brief self-report scale that provides additional information about the impact of adjunctive treatments on aspects of cognition and executive function, including attention, memory, and mental acuity. Subjects with MDD often report having difficulty functioning in this area. The KSS is a subject-reported assessment used to rate sleepiness on a scale of 1 to 9, ranging from "extremely alert" (1) to "very sleepy, great efforts to stay awake, fighting sleep" (9). The TEPS includes 18 items, with two subscales designed to distinguish between anticipatory and consummatory pleasure.

[0111] As used herein, unless otherwise stated, the term "aticaplant" refers to 3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide, i.e., the following compound:

[0112] [ka] Also known as JNJ-67953964, CERC-501, and LY-2456302. In some embodiments, "aticaplant" refers to the (S)-enantiomer of aticaplant, i.e., the following compound:

[0113] [ka] Also known as (S)-Aticaplant or (S)-3-Fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide. In other embodiments, Aticaplant used in the methods described herein is substantially free of the (R)-enantiomer having the following structure: (R)-Aticaplant or (R)-3-Fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide.

[0114] [ka]

[0115] In other embodiments, the Atika plant contains less than about 10% by weight of the (R)-enantiomer of Atika plant based on the weight of the Atika plant sample. In further embodiments, the Atika plant contains less than about 10% by weight, less than about 9% by weight, less than about 8% by weight, less than about 7% by weight, less than about 6% by weight, less than about 5% by weight, less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, less than about 1% by weight, less than about 0.5% by weight, less than about 0.1% by weight, less than about 0.005% by weight, or less than about 0.001% by weight of the (R)-enantiomer of Atika plant based on the weight of the Atika plant sample. In yet other embodiments, the Atika plant contains about 0.001 to about 10% by weight of the (R)-enantiomer of Atika plant based on the weight of the Atika plant sample. In still further embodiments, the Atika plant contains about 0.001 to about 10%, about 0.001 to about 5%, about 0.001 to about 1, about 0.001 to about 0.5, about 0.001 to about 0.1, about 0.1 to about 5, about 0.1 to about 1, about 0.1 to about 5, or about 0.5 to about 5 weight percent of the (R)-enantiomer of Atika plant, based on the weight of the Atika plant sample.

[0116] Pharmaceutically acceptable salts of acetophenone contemplated by the present invention can be easily selected by those skilled in the art. A "pharmaceutical acceptable salt" is a salt of acetophenone that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject. See generally GS Paulekuhn, "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J.Med.Chem., 2007, 50:6665-72; SM Berge, "Pharmaceutical Salts", J.Pharm.Sci., 1977, 66:1-19; and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharma- ceutically acceptable salts are salts that are pharmacologically effective and suitable for administration to a patient without undue toxicity, irritation, or allergic response.

[0117] Examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide (e.g., hydrobromide), iodide (e.g., hydroiodide), acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1, Examples of suitable salts include 4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate salts.

[0118] The methods described herein include administering to a patient an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof. The term "effective amount" as used herein means an amount of an active compound or pharmaceutical agent that induces a biological or medicinal response in a human tissue system that is sought by a researcher, physician, or other clinician, including the alleviation of one or more of the symptoms of the disease or disorder being treated. In some embodiments, aticaplant is utilized in an effective amount as determined by the attending physician. In other embodiments, other antidepressants are utilized in effective amounts, separately or in combination with aticaplant.

[0119] The amount of aticaplant for administration by the methods described herein may be determined by one of skill in the art and is provided on a free base basis of aticaplant unless otherwise stated. That is, the amount refers to the amount of aticaplant molecule administered, excluding, for example, solvent (such as in the form of a solvate) or counterion (such as in the form of a pharma- ceutically acceptable salt). In some embodiments, the effective amount of aticaplant is less than about 60 mg. In other embodiments, the effective amount of aticaplant is about 0.5 mg, about 1 mg, about 2 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg. In a further embodiment, the effective amount of Atikaplant is about 1 to about 50 mg, about 5 to about 50 mg, about 10 to about 50 mg, about 20 to about 50 mg, about 30 to about 50 mg, about 40 to about 50 mg, about 1 to about 45 mg, about 2 to about 45 mg, about 5 to about 45 mg, about 10 to about 45 mg, about 20 to about 45 mg, about 30 to about 45 mg, about 30 to about 40 mg, about 30 to about 35 mg, about 1 to about 40 mg, about 5 to about 40 mg, about 10 to about 40 mg, about 20 to about 40 mg, about 30 to about 40 mg, about 1 to about 35 mg, about 2 to about 35 mg. g, about 5 to about 35 mg, about 10 to about 35 mg, about 20 to about 35 mg, about 25 to about 35 mg, about 30 to about 35 mg, about 1 to about 30, about 2 to about 30 mg, about 5 to about 30 mg, about 10 to about 30 mg, about 20 to about 30 mg, about 25 to about 30 mg, about 1 to about 20 mg, about 2 to about 20 mg, about 5 to about 20 mg, about 10 to about 20 mg, about 15 to about 20 mg, about 1 to about 15 mg, about 2 to about 15 mg, about 5 to about 15 mg, about 10 to about 15 mg, about 1 to about 10 mg, about 2 to about 10 mg, or about 5 to about 10 mg. In yet another embodiment, the effective amount of the Atica plant is about 5 to about 15 mg. In yet a further embodiment, the effective amount of the Atica plant is about 10 mg. In yet a further embodiment, the effective amount of aticaplant is about 5 mg.

[0120] Advantageously, Aticaplant may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.

[0121] As described herein, in particular, the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaplant. Thus, in certain embodiments, the present disclosure relates to aticaplant or a pharma- ceutically acceptable salt thereof for use as described herein, where the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaplant. In further particular embodiments, the present disclosure also relates to the use of aticaplant or a pharma-ceutically acceptable salt thereof in the manufacture of a medicament as described herein, where the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaplant. In further particular embodiments, the present disclosure also relates to a package or pharmaceutical product as described herein, where the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaplant. Such antidepressant therapy may in particular be selected from selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or a combination thereof.

[0122] As described herein, aticaplant may be used as an adjunctive treatment, or in other words, in conjunction with, add-on to, or in combination with one or more antidepressants, for example, a patient may already be administered one or more antidepressants. Thus, in further specific embodiments, the present disclosure relates to aticaplant or a pharma- tically acceptable salt thereof for the uses described herein, including administration of aticaplant or a pharma- tically acceptable salt thereof as an adjunctive treatment with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure relates to aticaplant or a pharma- tically acceptable salt thereof for the uses described herein, including administration of aticaplant or a pharma- tically acceptable salt thereof in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure relates to aticaplant or a pharma- tically acceptable salt thereof for the uses described herein, including administration of aticaplant or a pharma- tically acceptable salt thereof in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure also relates to the use of aticaplant or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament as described herein, wherein the treatment comprises administering an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof as adjunctive treatment with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure also relates to the use of aticaplant or a pharma- ceutically acceptable salt thereof as described herein, wherein the treatment comprises administering an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure also relates to the use of aticaplant or a pharma- ceutically acceptable salt thereof as described herein, wherein the treatment comprises administering an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment instruct the administration of an effective amount of aticaplant or a pharma- ceutically acceptable salt thereof as adjunctive treatment with an effective amount of one or more antidepressants.In further specific embodiments, the present disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of aticaplant or a pharma- ceutical acceptable salt thereof in combination with an effective amount of one or more antidepressants. In further specific embodiments, the present disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of aticaplant or a pharma-ceutical acceptable salt thereof in combination with an effective amount of one or more antidepressants. The one or more antidepressants may be selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

[0123] As already mentioned, the present disclosure relates to aticaplant or a pharma- ceutically acceptable salt thereof for the uses described herein. In certain embodiments, aticaplant is S-aticaplant or a pharma- ceutically acceptable salt thereof. In further embodiments of the present disclosure, aticaplant, particularly S-aticaplant, or a pharma- ceutically acceptable salt thereof for the uses described herein is administered in an amount of about 2 to about 35 mg, more particularly about 10 mg, more particularly about 5 mg. In still further embodiments, aticaplant, particularly S-aticaplant, or a pharma- ceutically acceptable salt thereof for the uses described herein is administered orally. In still further particular embodiments, the present disclosure relates to aticaplant, particularly S-aticaplant, or a pharma- ceutically acceptable salt thereof for the uses described herein, administered once a day. The present disclosure also relates to the use of aticaplant in the manufacture of a medicament as described herein. In certain embodiments, aticaplant is S-aticaplant or a pharma- ceutically acceptable salt thereof. In further embodiments of the uses described herein, about 2 to about 35 mg of aticaplant, more particularly about 10 mg, more particularly about 5 mg, is administered. In yet further embodiments of the uses, aticaplant is administered orally. In yet further specific embodiments of the uses, aticaplant, particularly S-aticaplant, or a pharma- ceutically acceptable salt thereof, is administered once a day. In further specific embodiments, the present disclosure further relates to a package or pharmaceutical product described herein, wherein aticaplant is, in particular, S-aticaplant, or a pharma- ceutically acceptable salt thereof. In further embodiments of the packages or pharmaceutical products described herein, the instructions for treatment direct the administration of about 2 to about 35 mg of aticaplant, more particularly about 10 mg, more particularly about 5 mg. In further embodiments of the packages or pharmaceutical products described herein, the instructions for treatment of direct aticaplant, in particular S-aticaplant, or a pharma- ceutically acceptable salt thereof, are for oral administration. Moreover, in further specific embodiments of the package or pharmaceutical product described herein, the instructions for treatment of direct aticaplant, particularly S-aticaplant, or a pharma- ceutical acceptable salt thereof, are for once-daily administration.

[0124] Advantageously, administration of Atikaplant does not result in weight gain during treatment, including clinically relevant weight gain. Thus, in further specific embodiments, the present disclosure relates to Atikaplant or a pharma- ceutically acceptable salt thereof for the use described herein, wherein the patient does not experience weight gain during treatment with Atikaplant. In further specific embodiments, the present disclosure relates to the use defined herein, wherein the patient does not experience weight gain during treatment with Atikaplant. In further specific embodiments, the present disclosure further relates to the package or pharmaceutical product described herein, wherein the patient does not experience weight gain during treatment with Atikaplant. The patient's weight can be assessed, in particular, at the first administration of Atikaplant.

[0125] Also, unexpectedly, it was observed that patients do not experience a decline in sexual function during treatment with Atikaplant based on the evaluation at the first administration. Thus, in further specific embodiments, the present disclosure relates to Atikaplant or its pharma- ceutically acceptable salts for the use described herein, in which patients do not experience a decline in sexual function during treatment with Atikaplant. In further specific embodiments, the present disclosure relates to the use described herein, in which patients do not experience a decline in sexual function during treatment with Atikaplant. In further specific embodiments, the present disclosure relates to the package or pharmaceutical product described herein, in which patients do not experience a decline in sexual function during treatment with Atikaplant. Such term "sexual function" includes sexual drive, sexual arousal, vaginal lubrication, erection, orgasmic achievement, or orgasmic satisfaction. Sexual satisfaction can be assessed by methods known to those skilled in the art, for example, by applying the Arizona Sexual Experience Scale (ASEX).

[0126] As previously described, the patient has moderate or severe anhedonia. Anhedonia can be measured by an anhedonia scale, for example, the Snaith-Hamilton Pleasure Scale (SHAPS). Thus, in certain embodiments, the present disclosure relates to acicaplant or a pharma- ceutically acceptable salt thereof for use as described herein, wherein the patient's anhedonia is reduced by at least 40% as measured by the change from baseline in the total score on the anhedonia scale after 6 weeks of treatment with acicaplant, and more particularly, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks as measured by the change from baseline in the total score on the anhedonia scale. In further specific embodiments, the anhedonia scale is the Snaith-Hamilton Pleasure Scale (SHAPS). Thus, in certain embodiments, the disclosure relates to a use as described herein, wherein after 6 weeks of treatment with Atika plant, the patient's anhedonia is reduced by at least 40% as measured by a change from baseline in the total score on the Anhedonia Scale, more particularly, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks as measured by a change from baseline in the total score on the Anhedonia Scale. In further particular embodiments, the Anhedonia Scale is the Snaith-Hamilton Pleasure Scale (SHAPS). In further particular embodiments, the disclosure relates to a package or pharmaceutical product as described herein, wherein the patient's anhedonia is reduced by at least 40% as measured by a change from baseline in the total score on the Anhedonia Scale after 6 weeks of treatment with Atika plant, more particularly, the subject's anhedonia is reduced within about 3 weeks to about 6 weeks as measured by a change from baseline in the total score on the Anhedonia Scale. In a further particular embodiment, the anhedonia scale is the Snaith-Hamilton Anhedonia Scale (SHAPS).

[0127] Methods and Uses Involving Esketamine In one aspect of the invention, a method of treating depression is provided comprising, consisting of, or consisting essentially of administering an effective amount of esketamine to a patient in need thereof, wherein the patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

[0128] In a further aspect of the invention, there is provided a method of treating depression comprising, consisting of, or consisting essentially of administering an effective amount of esketamine to a patient in need thereof, wherein the patient is biomarker signature positive when a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

[0129] Further described herein is esketamine for use in the treatment of depression, comprising, consisting of, or consisting essentially of administering an effective amount of esketamine to a patient in need of treatment for depression, wherein the patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

[0130] Further described herein is esketamine for use in the treatment of depression, comprising, consisting of, or consisting essentially of administering an effective amount of esketamine to a patient in need of treatment for depression, wherein the patient is biomarker signature positive, and the patient is biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

[0131] In certain embodiments, described herein are methods of identifying a patient as a candidate for treatment with esketamine if the subject is biomarker signature positive, where the patient is identified as being biomarker signature positive if a biological sample obtained from the patient is identified as having at least one of: (a) a level of CRP higher than a reference CRP level, and (b) (i) a level of TNF-α higher than a reference TNF-α level, and (ii) a level of sIL6R higher than a reference sIL6R level. In certain embodiments, the method further comprises administering to the patient an effective amount of esketamine.

[0132] It will be understood that for each of the methods of treatment described herein, the method of treatment may also be configured as a method of manufacturing a medicament for the treatment of the described indication, or as esketamine for use in the treatment of the described indication.

[0133] Methods of maintaining a stable remission or stable response achieved by a patient with depression after administration of a therapeutically effective amount of esketamine during an initial dosing phase are also described, comprising continuously administering a therapeutically effective amount of esketamine for at least five months during a subsequent dosing phase.

[0134] In embodiments of any of the foregoing treatment methods, the method has an induction phase, optionally followed by a maintenance phase, where the induction phase includes induction phase treatment sessions at a given frequency, and the maintenance phase includes maintenance phase treatment sessions that are administered less frequently to the patient.

[0135] In some embodiments, methods for long-term treatment of depression in a patient are also provided. These methods include administering a therapeutically effective amount of esketamine to a patient in need of treatment for at least 6 months. Desirably, the patient's cognitive performance remains stable based on baseline measurements after 6 months of treatment. In some embodiments, the treatment may be for a duration of at least about 1 year, at least about 18 months, or at least about 2 years. For example, long-term treatment may include a duration range of about 6 months to about 2 years. Treatment may also be continued for longer periods, including, but not limited to, 4, 5, 6, 7, 8, 9, 10 years or more, as determined by the attending physician. In some embodiments, esketamine is initially administered twice weekly for up to 4 weeks during an induction phase, and then administered less frequently than twice weekly.

[0136] In further embodiments, the method includes intranasally administering to the patient about 28 mg to about 84 mg of esketamine per induction phase treatment session, where the induction phase treatment sessions occur at a frequency of twice weekly during the induction phase, and optionally intranasally administering to the patient about 56 mg to about 84 mg of esketamine per maintenance phase treatment session, where the maintenance phase treatment sessions occur at a frequency of once weekly or once every other week. In certain embodiments, the induction phase has a duration of about 4 weeks.

[0137] In certain embodiments, about 56 or about 84 mg of esketamine is administered per induction treatment session, hi further embodiments, about 56 or about 84 mg of esketamine is administered per maintenance treatment session.

[0138] In certain embodiments, esketamine may be administered in combination with one or more antidepressants, preferably in combination with 1-3 antidepressants, and more preferably in combination with 1-2 antidepressants, as described herein.

[0139] In certain embodiments, esketamine may be administered in combination with one or more antidepressants, further in combination with one or more atypical antipsychotics, as described herein.

[0140] In further embodiments, the disclosure is directed to combination therapies comprising esketamine and one or more antidepressants, where esketamine is administered as an acute treatment, hi other embodiments, the disclosure is directed to combination therapies comprising esketamine and one or more antidepressants, where esketamine is administered as an acute treatment and one or more antidepressants are administered as a chronic treatment.

[0141] In other embodiments, such as during the induction phase, esketamine may be used as a monotherapy and may not be used in combination with any other active compounds.

[0142] As used herein, unless otherwise specified, the term “esketamine” refers to the (S)-enantiomer of ketamine, i.e., the compound of formula (I):

[0143] [ka] "Esketamine" also refers to a salt, e.g., a chloride salt, such as the hydrochloride salt, of the (S)-enantiomer of ketamine, i.e., the compound of formula (II):

[0144] [ka] “(S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride” is intended to mean a chloride salt, such as the hydrochloride salt of the compound of the formula:

[0145] In some embodiments, esketamine is the (R)-enantiomer of ketamine, i.e., formula (III):

[0146] [ka] In other embodiments, the esketamine contains less than about 10% by weight of the (R)-enantiomer of ketamine based on the weight of the esketamine sample. In further embodiments, the esketamine contains less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.1%, less than about 0.005%, or less than about 0.001% by weight of the (R)-enantiomer of ketamine based on the weight of the esketamine sample. In yet other embodiments, the esketamine contains from about 0.001 to about 10% by weight of the (R)-enantiomer of ketamine based on the weight of the esketamine sample. In still further embodiments, the esketamine contains about 0.001 to about 10%, about 0.001 to about 5%, about 0.001 to about 1, about 0.001 to about 0.5, about 0.001 to about 0.1, about 0.1 to about 5, about 0.1 to about 1, about 0.1 to about 5, or about 0.5 to about 5% by weight of the (R)-enantiomer of esketamine based on the weight of the esketamine sample.

[0147] The term "esketamine" may also include other pharma- ceutically acceptable salts thereof, which may be readily selected by one of ordinary skill in the art. A "pharma-ceutically acceptable salt" is intended to mean a salt of esketamine that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally GS Paulekuhn, "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J. Med. Chem., 2007, 50:6665-72; SM Berge, "Pharmaceutical Salts", J Pharm Sci., 1977, 66:1-19; and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharma- ceutically acceptable salts are salts that are pharmacologically effective and suitable for administration to a patient without undue toxicity, irritation, or allergic response.

[0148] Examples of other pharma- ceutically acceptable salts include sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide (e.g., hydrobromide), iodide (e.g., hydroiodide), acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate, 1-methylbut ... Examples of suitable salts of esketamine include 1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate. In particular, the salts of esketamine are chloride salts, such as the hydrochloride salt.

[0149] In certain embodiments, esketamine is administered intranasally. In other embodiments, esketamine is administered intranasally as its corresponding hydrochloride salt. In further embodiments, esketamine is administered intranasally as its corresponding hydrochloride salt in a 16.14% weight / volume solution (corresponding to 14% weight / volume of esketamine base).

[0150] In some embodiments, esketamine is delivered from the intranasal device in two or more sprays during the induction and / or maintenance phases. In certain aspects, the method further comprises administering a therapeutically effective amount of an oral antidepressant to the patient during the induction and / or maintenance phases. In certain aspects, esketamine is administered as its corresponding hydrochloride salt during the induction and / or maintenance phases.

[0151] In certain embodiments, esketamine is administered intranasally in a solution containing 161.4 mg / mL esketamine hydrochloride (equivalent to 140 mg / mL esketamine base), 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / mL citric acid at a pH of 4.5 in water. In other embodiments, esketamine is administered intranasally, with intranasal delivery of 100 μL of a solution containing 161.4 mg / mL esketamine hydrochloride (equivalent to 140 mg / mL esketamine base), 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / mL citric acid at a pH of 4.5 in water. In one particular embodiment, esketamine is delivered intranasally using a nasal spray pump that delivers 100 μL of a solution containing 161.4 mg / mL esketamine hydrochloride (equivalent to 140 mg / mL esketamine base), 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / mL citric acid at a pH of 4.5 in water.

[0152] Generally, one pump from the nasal spray device may be configured to deliver about 50 μL to about 200 μL (including about 60 μL, about 70 μL, about 80 μL, about 90 μL, about 100 μL, about 110 μL, about 120 μL, about 130 μL, about 140 μL, about 150 μL, about 160 μL, about 170 μL, about 180 μL, and about 200 μL) of esketamine solution to a subject's nostril. Thus, two pumps deliver about 100 μL to about 400 μL to a subject.

[0153] In certain embodiments, the patient in need of treatment with a therapeutically effective amount of esketamine is a patient suffering from an episode of depression (e.g., major depressive disorder). In other embodiments, the patient in need of treatment is suffering from an episode of depression (e.g., major depressive disorder), and the episode of depression (e.g., major depressive disorder) has not responded to treatment with at least two oral antidepressants (i.e., the patient has not responded to treatment with at least two oral antidepressants). In other embodiments, the elderly patient in need of treatment is suffering from an episode of depression (e.g., major depressive disorder), and the episode of depression (e.g., major depressive disorder) has not responded to treatment with two oral antidepressants (i.e., the elderly patient has not responded to treatment with two oral antidepressants).

[0154] The esketamine and the antidepressant may be administered via the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intranasal (in), intramuscular (im), subcutaneous (sc), transdermal, buccal, or rectal. In some embodiments, the esketamine is administered intranasally.

[0155] A therapeutically effective amount of esketamine and / or an antidepressant may be administered during the early and / or late stages, as described herein. In some embodiments, the therapeutically effective amount of esketamine is about 20 to about 100 mg. In other embodiments, the therapeutically effective amount of esketamine is about 30 to about 90 mg. In further embodiments, the therapeutically effective amount of esketamine is about 40 to about 80 mg. In still other embodiments, a therapeutically effective amount of esketamine is about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or about 100 mg. In further embodiments, the therapeutically effective amount is about 28 mg, about 56 mg, or about 84 mg. In other embodiments, the therapeutically effective amount is about 56 mg or about 84 mg. In yet a further embodiment, the therapeutically effective amount of esketamine is about 28 mg. In other embodiments, the therapeutically effective amount of esketamine is about 56 mg. In yet a further embodiment, the therapeutically effective amount of esketamine is about 84 mg. Unless otherwise specified, the amount of esketamine corresponds to the free base of esketamine.

[0156] As mentioned above, a method for treating depression in a patient is described. The method includes administering esketamine in one, two, or optionally three phases, i.e., initial and subsequent administration phases. In some embodiments, the phases include an initial induction phase, an extended induction phase, a maintenance phase, or any combination thereof. Thus, an effective amount of esketamine is administered in each phase. A physician can evaluate the patient's condition and determine the most beneficial initial / induction and maintenance dose for the patient from the dosage range and administration frequency specified herein. The effective amount of esketamine can be the same or different in each phase.

[0157] The methods described herein allow for optimizing the dose of esketamine for administration to patients with or susceptible to depression during the "optimization phase." Optimization can be considered as part of the maintenance phase following the induction phase. In some embodiments, the methods described herein do not require adjustment of the dosage of esketamine. Indeed, esketamine may be administered at the least dosing frequency at which an esketamine response is observed and maintained in the patient during the phases described herein (e.g., induction and maintenance phases). An effective amount of esketamine has been found to be about 28 to about 84 mg.

[0158] As used herein, an "induction phase" or "acute administration phase" is the period during which esketamine is first administered to a patient. In some embodiments, the induction phase is long enough to achieve a robust and stable reduction in depressive symptoms. The induction phase may depend on factors including, but not limited to, the particular patient and / or the patient's gender, age, weight, administration time, administration frequency, and associated diseases. The induction phase may include an initial induction phase and an extended induction phase. The total induction period (initial and extended periods combined) may be about 4 to about 12 weeks, about 4 to about 11 weeks, about 4 to about 10 weeks, about 4 to about 9 weeks, about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, about 5 to about 12 weeks, about 5 to about 11 weeks, about 5 to about 10 weeks, about 5 to about 9 weeks, about 5 to about 8 weeks, about 5 to about 7 weeks, about 5 to about 6 weeks, about 6 to about 12 weeks, about 6 to about 11 weeks, about 6 to about 10 weeks, about 6 to about 9 weeks, about 6 to about 8 weeks, about 7 to about 12 weeks, about 7 to about 11 weeks, about 7 to about 10 weeks, about 7 to about 9 weeks, about 8 to about 12 weeks, about 8 to about 11 weeks, or about 8 to about 10 weeks. In some embodiments, the total induction period is about 4 to about 8 weeks.

[0159] In the initial induction period, the patient is administered a therapeutically effective amount of esketamine at a given frequency of at least twice a week. In some embodiments, the patient is administered a therapeutically effective amount of esketamine at a given frequency of three times a week. As long as the administration is three times a week, the administration is performed on days 1, 3, and 5 ± 1 of the week. The initial induction phase is typically a period during which the patient is shown to be responsive to treatment but is not ready to progress to the maintenance phase. At a point therein, the patient's response is evaluated by a person skilled in the art. In some embodiments, the patient's response is evaluated daily. In other embodiments, the patient's response is evaluated twice a week. In further embodiments, the patient's response is evaluated every other day. In yet other embodiments, the patient's response is evaluated at the end of the initial induction phase. Typically, the patient's response can be evaluated using techniques and tests known to those skilled in the art. In some embodiments, the patient's MADRS score is determined and used as a determination as to whether the initial induction phase has ended. The initial induction phase is of such length that it desirably achieves a reduction in depressive symptoms. In some embodiments, the initial induction phase is about 1 to about 4 weeks in duration. In other embodiments, the induction phase is up to about 1 week, up to about 2 weeks, up to about 3 weeks, or up to about 4 weeks in duration. In further embodiments, the initial induction period is about 1 to about 3 weeks, about 1 to about 2 weeks, about 2 to about 4 weeks, about 2 to about 3 weeks, about 3 to about 4 weeks, 1 week, 2 weeks, 3 weeks, 4 weeks, up to 1 week, up to 2 weeks, up to 3 weeks, or up to 4 weeks. The effective amount of esketamine administered during the initial induction phase can be determined by the attending physician. In some embodiments, the effective amount of esketamine administered during the initial induction phase is about 28 mg. In some embodiments, the effective amount of esketamine administered during the initial induction phase is about 56 mg. In other embodiments, the effective amount of esketamine administered during the initial induction phase is about 84 mg.

[0160] As used herein, the term "twice weekly" refers to a frequency of two times in a one week (7 day) period. For example, "twice weekly" may refer to the administration of esketamine herein. "Twice weekly" may also refer to a frequency of monitoring a patient in one or more phases discussed herein. In some embodiments, twice weekly refers to a frequency that is the first and second days of the week. In other embodiments, twice weekly refers to a frequency that is the first and third days of the week. In further embodiments, twice weekly refers to a frequency that is the first and fourth days of the week. In yet other embodiments, twice weekly refers to a frequency that is the first and fifth days of the week. "Day 1" may be any day of the week, including Sunday, Monday, Tuesday, Wednesday, Thursday, Friday, or Saturday. Typically, with respect to the administration of esketamine, twice weekly refers to a frequency that is the first and fourth days of the week. To the extent there is an erroneous administration, a dose may be taken as soon as possible thereafter, and the prescribed regimen may then be continued.

[0161] In some patient populations (such as the elderly), the reduction of depressive symptoms during the initial induction phase is insufficient, necessitating an extended induction phase. In the extended initial induction phase, continuous administration of a therapeutically effective amount of esketamine is performed at a given frequency of at least twice a week. At a point therein, the patient's response is again evaluated by a person skilled in the art. In some embodiments, the patient's response is evaluated daily. In other embodiments, the patient's response is evaluated twice a week. In further embodiments, the patient's response is evaluated every other day. Typically, the patient's response can be evaluated using techniques and tests known to those skilled in the art. In some embodiments, the patient's MADRS score is determined and used as a determination as to whether the extended induction phase has ended. The extended induction phase is desirably of such length to achieve a substantial reduction in depressive symptoms, thus achieving a substantially complete response to esketamine.

[0162] As used herein, the term "substantially complete response to esketamine" refers to a patient having a reduction in MADRS score from baseline to at least a 50% improvement from baseline. In some embodiments, a substantially complete response to esketamine refers to a patient having either an at least 50% improvement from baseline or a MADRS score of about -20 below the patient baseline score. In other embodiments, a substantially complete response includes a reduction in MADRS score of about -20 or less, -19 or less, -18 or less, -17 or less, -16 or less, -15 or less, -14 or less, -13 or less, -12 or less, -11 or less, or -10 or less. In further embodiments, a substantially complete response results in a patient having a reduction of about -15 to about -20 from the MADRS baseline score. A substantially complete response to esketamine may also be obtained when the patient's MADRS score is reduced by about 50% from the MADRS score at the start of treatment. Such a substantially complete response may be observed at any time during esketamine treatment. In some embodiments, a substantially complete response is observed when the patient has a reduction in MADRS total score from baseline 4 hours after treatment, hi other embodiments, a substantially complete response is observed when the patient has a reduction in MADRS total score from baseline 2 days after treatment.

[0163] The extended induction phase is a period of time that results in a substantially complete response to esketamine. In some embodiments, the extended induction phase is from about 1 to about 8 weeks. In other embodiments, the extended induction phase is for a period of up to about 1 week, up to about 2 weeks, up to about 3 weeks, up to about 4 weeks, up to about 5 weeks, up to about 6 weeks, up to about 7 weeks, or up to about 8 weeks. In further embodiments, the extended induction period is about 1 to about 8 weeks, about 1 to about 7 weeks, about 1 to about 6 weeks, about 1 to about 5 weeks, about 1 to about 4 weeks, about 1 to about 3 weeks, about 2 to about 8 weeks, about 2 to about 7 weeks, about 2 to about 7 weeks, about 2 to about 6 weeks, about 2 to about 5 weeks, about 2 to about 4 weeks, about 3 to about 8 weeks, about 3 to about 7 weeks, about 3 to about 6 weeks, about 3 to about 5 weeks, about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, about 5 to about 8 weeks, about 5 to about 7 weeks, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks. The effective amount of esketamine administered during the extended induction period can be determined by the attending physician. In some embodiments, the effective amount of esketamine administered during the extended induction period is about 56 mg. In other embodiments, the effective amount of esketamine administered during the extended induction phase is about 84 mg.

[0164] Administration may further include an optimization / maintenance phase following the induction phase, where after the patient achieves a substantially complete response to esketamine during the induction phase, esketamine is administered less frequently than twice weekly during the optimization / maintenance phase, in some embodiments, the frequency of administration during the optimization / maintenance phase is once weekly, once every two weeks, once monthly, or a combination thereof.

[0165] At any stage during one or more of the induction, optimization, or maintenance phases, the patient's response to treatment may be evaluated using the techniques described herein. This evaluation may be performed until the patient is deemed by those skilled in the art to have achieved a suitable response to the treatment regimen. In some embodiments, the induction period may be said to be complete when the patient's MADRS score is reduced by 50% or more from baseline, or from about 20 to about 13. In other embodiments, the patient's MADRS score may be about 19, about 18, about 17, about 16, about 15, about 14, or about 13. Patients with a MADRS score of 12 or less are considered to be in remission and should be moved to or maintained in the maintenance phase if stable for 4 weeks.

[0166] At the end of the induction phase or extended induction phase, the treating physician should evaluate the patient to optimize the dosage and frequency of any subsequent administration phase, such as a "maintenance phase" or "long-term therapy phase." It is expected that the frequency of intranasal treatment during the subsequent administration, such as the maintenance phase, will be reduced from the frequency during the induction phase or extended induction phase (at least twice a week) to once a week administration for at least 4 weeks. In some embodiments, the subsequent administration, such as the maintenance phase, is for at least about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, 1 year, or about 2 years. In some embodiments, the continued administration of esketamine during the subsequent administration phase is for at least 6 months. In other embodiments, the continued administration of esketamine during the subsequent administration phase is for at least 1 year. In further embodiments, the frequency of administration during the subsequent dosing phase is once every week, or once every two weeks, or a combination thereof. In yet other embodiments, the frequency and effective amount of administration of esketamine during the subsequent dosing phase is the minimum frequency and amount to maintain stable remission or stable response.

[0167] Subsequent administrations, such as maintenance periods, may include longer periods depending on the patient's condition. In some embodiments, these longer periods may be at least about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, or more than about 10 years, including indefinitely. For example, for patients diagnosed with TRD, treatment may be indefinite. In other embodiments, the treatment frequency is reduced to every other week. In further embodiments, the treatment frequency is reduced to every 3 weeks. In yet other embodiments, the treatment frequency is reduced to once a month. The patient is maintained on schedule until the patient achieves remission, maintains response, or fails treatment. If the patient achieves remission or maintains response with weekly treatment for at least 4 weeks, the frequency of intranasal treatment sessions can be reduced to a biweekly maintenance dose based on the severity of depressive symptoms, and in some patient populations, the treatment frequency can be reduced to about once every 3 or 4 weeks as described above.

[0168] One of skill in the art will understand that the maintenance phase described herein can continue until further treatment is no longer necessary, as indicated, for example, by long-term remission of depression (e.g., including remission of one or more symptoms associated with depression), improvement in social and / or occupational functioning to normal or pre-morbid levels, or other known measures of depression.

[0169] An effective amount of esketamine is administered to the patient during the maintenance phase. As described above, the amount of esketamine administered during the maintenance phase is an amount that causes a biological or pharmaceutical response in the tissue systems described above with respect to the induction phase. In certain embodiments, the effective amount of esketamine is an amount that maintains the pharmacodynamic steady state of esketamine achieved in the induction phase. In other embodiments, if depressive symptoms begin to worsen with biweekly, 3-weekly, or 4-weekly treatment, the administration of esketamine will be increased to stabilize the patient. For example, if a patient is receiving biweekly administration and their symptoms begin to worsen, esketamine can be administered once a week during the maintenance phase to maintain response. Again, the patient's response can be reassessed at any time during the maintenance phase.

[0170] In elderly patients, the recommended dose of esketamine is about 28 to about 84 mg. It is recommended that the initial dose (in the first treatment session) be about 28 mg of esketamine. Based on the efficacy and tolerability of the about 28 mg dose, the dose in the next treatment session may remain at about 28 mg or may be increased to about 56 mg. Depending on the efficacy and tolerability of the about 56 mg dose, the dose in the subsequent treatment session may remain at about 56 mg or may be increased to about 84 mg, or may be reduced to about 28 mg. Depending on the tolerability of the about 84 mg dose, the dose in the subsequent treatment session may remain at about 84 mg or may be reduced to about 56 mg.

[0171] In patients with hepatic impairment, the recommended dose of esketamine is about 28 to about 56 mg. The initial dose (in the first treatment session) is recommended to be about 28 mg of esketamine. Based on the efficacy and tolerability of the about 28 mg dose, the dose in the next treatment session may remain at about 28 mg or may be increased to about 56 mg. Because esketamine is extensively metabolized in the liver, physicians should regularly monitor patients with hepatic impairment for drug tolerance.

[0172] In the treatment of patients with major depressive disorder who have suicidal ideation and are at imminent risk of suicide, dosing is more aggressive due to the severity of the condition. The method includes administering esketamine during one or two phases, namely an initial induction phase and, optionally, in certain circumstances, a maintenance phase. Due to the imminent risk to the patient's life, the initial dose of esketamine is administered at the highest effective dose of esketamine that the patient can tolerate twice a week during the induction phase. In some embodiments, the patient continues therapy with an existing (i.e., currently initiated) antidepressant simultaneously with the initiation of therapy with esketamine during the induction phase. In other embodiments, the patient begins therapy with a new antidepressant simultaneously with the initiation of therapy with esketamine during the induction phase. In further embodiments, the patient continues therapy with a previously administered antidepressant simultaneously with the initiation of therapy with esketamine during the induction phase. The antidepressant should be administered in a manner appropriate to the patient's condition / health and as described on the label for the treatment of MDD. The induction phase should be about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, and most preferably about 4 weeks. At the end of the induction phase, if the patient is responding adequately to treatment or is in remission, esketamine administration should be discontinued. The patient should be monitored to ensure that the patient remains stable or is in remission on the antidepressant alone. If the patient is not stabilized on the first combination of esketamine and antidepressant or fails treatment with the antidepressant initiated with esketamine after cessation of esketamine administration, a second induction phase may be initiated.

[0173] In the second induction phase, the patient is restarted with esketamine at the highest tolerated dose and simultaneously with a second new antidepressant. Alternatively, the patient is restarted with esketamine at the highest tolerated dose and simultaneously with the same antidepressant used during the previous induction phase. Esketamine is administered twice weekly. The antidepressant is administered in a manner appropriate to the patient's condition / health and as directed on the label for the treatment of MDD. The second induction phase should be about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, and most preferably about 4 weeks. At the end of the second induction phase, if the patient is responding adequately to treatment or in remission, esketamine administration should be discontinued and the patient should be monitored to ensure that the patient remains stable / or is in stable remission on the antidepressant alone. If the patient does not stabilize or fails treatment with the antidepressant initiated with esketamine after cessation of esketamine administration, a third induction phase may be initiated.

[0174] In the third induction phase, the patient is restarted with esketamine at the highest tolerated dose and simultaneously with a third new antidepressant. Alternatively, the patient is restarted with esketamine at the highest tolerated dose and simultaneously with the same antidepressant used during the second induction phase. Esketamine is administered twice weekly. The antidepressant is administered in a manner appropriate to the patient's condition / health and as directed on the label for the treatment of MDD. The third induction phase should be about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, and most preferably about 4 weeks. At the end of the third induction phase, the patient is now certified as a TRD patient, and therefore the patient proceeds to the maintenance phase designated for TRD. The methods described herein allow for optimizing the dosage of esketamine for administration to patients with depression or susceptible to depression. In some embodiments, the methods described herein do not require adjustment of the dosage of esketamine.

[0175] In general, the patient may be resumed with the highest tolerated dose of esketamine and at the same time with the same antidepressant used during any previous induction phase (including the antidepressant with which the patient did not stabilize or otherwise failed treatment). For example, in a method for treating treatment-resistant depression in a patient in which the patient has not responded to at least two oral antidepressants in a current depressive episode, the patient may be administered esketamine alone or at least twice a week with a first oral antidepressant that is the same or different from the previously ineffective oral antidepressant in the first induction phase. To the extent that the patient does not achieve a substantially complete response to esketamine, the patient may be resumed with the highest tolerated dose of esketamine alone or at the same time with a second oral antidepressant that is the same or different from the first oral antidepressant in the second induction phase. To the extent that the patient achieves a substantially complete response to esketamine during the second induction phase, the patient may then be administered a therapeutically effective amount of esketamine less than twice a week during the subsequent maintenance phase.

[0176] If one or more (e.g., two) doses of esketamine are not administered during any of the phases described herein, the next dose will be scheduled when possible based on the dosing frequency regimen. If more than two doses are not administered according to clinical judgment, an adjustment in the dose or frequency of esketamine may be necessary.

[0177] Advantageously, esketamine may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or four times a day, preferably two times a day. Typically, divided doses should be administered at shorter intervals. In some embodiments, divided doses are administered within about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, about 1 minute, or less of each other. Additionally, in a flexible dosing regimen, patients may be administered daily, twice a week, once a week, once every other week, or once a month. For example, one dose of esketamine is administered on day 1 and another dose of esketamine is administered on day 2, or one dose of esketamine is administered on day 1 and another dose of esketamine is administered on day 3, or one dose of esketamine is administered on day 1 and another dose of esketamine is administered on day 4, or one dose of esketamine is administered on day 1 and another dose of esketamine is administered on day 5. Additionally, esketamine is preferably administered in intranasal form via topical use of a suitable intranasal vehicle, such as a nasal spray pump.

[0178] A representative nasal spray device is disclosed in U.S. Patent No. 6,321,942, which is incorporated herein by reference. For example, a disposable sprayer for discharging successive partial discharges as a spray can be utilized to carry out the methods disclosed herein. Typically, such a device allows for spraying of the medicament into both nostrils of a patient in two successive strokes. The container may be a ready-to-use device in which the medicament is discharged from a media container. The device may typically separate the first discharge stroke from the second discharge stroke to prevent complete emptying of the media container in a single motion. The device may take the form of a two-stroke disposable pump that is discarded after a single use and allows for individual partial discharges with high dosing accuracy and reliability.

[0179] In one embodiment, the nasal spray device is a single-use device that delivers a total of 28 mg of esketamine in two sprays (one spray per nostril). The device may be operated by the patient under the supervision of a medical professional. In terms of dosage, one device may be used for a 28 mg dose, two devices for a 56 mg dose, or three devices for an 84 mg dose. It is also preferred to have a 5 minute interval between the use of each device. As described in Example 1, time 0 is defined as the time of administration of the first intranasal spray from the first intranasal device into one nostril.

[0180] As used herein, AD = antidepressants, ESK = esketamine nasal spray, PHQ-9 = Patient Adherence Questionnaire, SDS = Sheehan Disability Scale, CGI-S = Clinical Global Impression-Severity, MADRS = Montgomery-Åsberg Depression Rating Scale, SD = standard deviation, C-SSRS = Columbia Suicide Severity Rating Scale, MDD = major depressive disorder, MGH-ATRQ = Massachusetts General Hospital-Antidepressant Treatment History Questionnaire, TRD = treatment-resistant depression.

[0181] Pharmaceutical Compositions Methods for formulating pharmaceutical compositions are described in many publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al., all published by Marcel Dekker, Inc.

[0182] In one embodiment, the preferred pharmaceutical composition comprises Aticaplant as an active ingredient, thoroughly mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which may take a wide variety of forms depending on the form of preparation desired for administration. Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the British Pharmaceutical Association.

[0183] In a further embodiment of the preferred pharmaceutical composition, S-ketamine hydrochloride as the active ingredient is thoroughly mixed with a pharmaceutical carrier, preferably water, according to conventional pharmaceutical compounding techniques, which may take a variety of forms depending on the form of preparation desired for administration. Suitable pharma- ceutically acceptable carriers are well known in the art.

[0184] One suitable aqueous formulation of S-ketamine comprises water and S-ketamine, wherein S-ketamine is present in an amount ranging from about 25 mg / mL to about 250 mg / mL, preferably from about 55 mg / mL to about 250 mg / mL, or from about 100 mg / mL to about 250 mg / mL, or any amount or range therein, based on the total volume of the pharmaceutical composition. Preferably, S-ketamine is present in an amount ranging from about 150 mg / mL to about 200 mg / mL, or any amount or range therein. More preferably, S-ketamine is present in an amount ranging from about 150 mg / mL to about 175 mg / mL, or any amount or range therein. More preferably, S-ketamine is present in an amount ranging from about 160 mg / mL to about 163 mg / mL, for example, in an amount of about 161.4 mg / mL.

[0185] Another suitable aqueous formulation of S-ketamine comprises water and S-ketamine, wherein the S-ketamine is present in an amount ranging from about eq. 100 mg / mL equivalent to about 250 mg / mL equivalent, or any amount or range therein, based on the total volume of the pharmaceutical composition. Preferably, the S-ketamine is present in an amount ranging from about eq. 125 mg / mL equivalent to about eq. 180 mg / mL equivalent, or any amount or range therein. More preferably, the S-ketamine is present in an amount ranging from about eq. 140 mg / mL equivalent to about eq. 160 mg / mL equivalent, or any amount or range therein, for example, about eq. 140 mg / mL equivalent.

[0186] The pharmaceutical composition suitable for use herein is preferably an aqueous formulation.As used herein, unless otherwise specified, the term "aqueous" means that the main liquid component of the formulation is water.Preferably, water comprises more than about 80% by weight of the liquid component of the pharmaceutical composition, more preferably more than about 90% by weight, more preferably more than about 95% by weight, more preferably about 98% by weight.

[0187] In pharmaceutical compositions suitable for use herein, the water content of the composition is in the range of 85±14% by weight, more preferably 85±12% by weight, even more preferably 85±10% by weight, most preferably 85±7.5% by weight, especially 85±5% by weight, based on the total weight of the composition.

[0188] In pharmaceutical compositions suitable for use herein, preferably the water content of the composition is in the range of 90±14% by weight, more preferably 90±12% by weight, even more preferably 90±10% by weight, most preferably 80±7.5% by weight, especially 90±5% by weight, based on the total weight of the composition.

[0189] In another pharmaceutical composition for use herein, the water content of the composition is within the range of 95±4.75% by weight, more preferably 95±4.5% by weight, even more preferably 95±4% by weight, still more preferably 95±3.5% by weight, most preferably 95±3% by weight, especially 95±2.5% by weight, based on the total weight of the composition.

[0190] In another pharmaceutical composition for use herein, the water content of the composition is in the range of 75 to 99.99% by weight, more preferably 80 to 99.98% by weight, even more preferably 85 to 99.95% by weight, still more preferably 90 to 99.9% by weight, most preferably 95 to 99.7% by weight, especially 96.5 to 99.5% by weight, based on the total weight of the composition.

[0191] In another pharmaceutical composition for use herein, the composition further comprises one or more buffering agents and / or buffering systems (ie, conjugate acid-base pairs).

[0192] As used herein, the term "buffering agent" is intended to mean any solid or liquid composition (preferably an aqueous liquid composition) that, when added to an aqueous formulation, adjusts the pH of the formulation. Those skilled in the art will recognize that a buffering agent may adjust the pH of an aqueous formulation in any direction (towards a more acidic, more basic, or more neutral pH). Preferably, the buffering agent is pharma- ceutically acceptable.

[0193] Suitable examples of buffers that may be used in the aqueous formulation include, but are not limited to, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, malic acid, lactic acid, fumaric acid, etc. Preferably, the buffer or buffer system is selected from the group consisting of NaOH, citric acid, sodium dihydrogen phosphate, and disodium hydrogen phosphate.

[0194] In one embodiment, the buffering agent is selected to adjust the pH of the S-ketamine hydrochloride pharmaceutical composition (e.g., an aqueous formulation described herein) to a pH in the range of about pH 3.5 to about pH 6.5, or any amount or range therein. Preferably, the buffering agent is selected to adjust the pH of the S-ketamine hydrochloride composition to a pH in the range of about pH 4.0 to about pH 5.5, or any amount or range therein, more preferably, to a range of about pH 4.5 to about pH 5.0, or any amount or range therein.

[0195] Preferably, the concentrations of the buffer and buffer system, preferably NaOH, respectively, are adjusted to provide sufficient buffering capacity.

[0196] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising S-ketamine hydrochloride, water, and a buffering agent or buffering system, preferably NaOH, wherein the buffering agent or buffering system is present in an amount sufficient to obtain a formulation having a pH in the range of about pH 4.0 to about pH 6.0, or any amount or range therein.

[0197] Optionally, the pharmaceutical composition may contain a preservative. As used herein, unless otherwise specified, the terms "antimicrobial preservative" and "preservative" preferably refer to any substance that is usually added to a pharmaceutical composition to protect the pharmaceutical composition against microbial degradation or microbial growth. In this regard, microbial growth typically plays an essential role. That is, the preservative serves the main purpose of avoiding microbial contamination. In some aspects, it may be desirable to avoid any microbial effect on the active ingredient and excipients, respectively, that is, to avoid microbial degradation.

[0198] Representative examples of preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, sorbic acid, and potassium sorbate.

[0199] Due to its preservative properties, it is preferred that preservatives in the pharmaceutical compositions used herein are completely absent when the content of S-ketamine hydrochloride is high enough so that the desired shelf life or stability in use can be achieved by the presence of the drug itself.Preferably, under these circumstances, the concentration of S-ketamine hydrochloride is at least eq.120 mg / mL equivalent, preferably in the range of about 120 mg / mL equivalent to about 175 mg / mL equivalent, or any amount or range therein, more preferably in the range of about 125 mg / mL equivalent to about 150 mg / mL equivalent, or any amount or range therein, such as about 126 mg / mL equivalent or about 140 mg / mL equivalent.

[0200] As used herein, the terms "penetration agent," "penetration enhancer," and "penetrant" refer to any substance that increases or enhances the absorption and / or bioavailability of an active ingredient (e.g., S-ketamine hydrochloride) of a pharmaceutical composition. Preferably, the penetrant increases or enhances the absorption and / or bioavailability of an active ingredient (e.g., S-ketamine hydrochloride) of a pharmaceutical composition following nasal administration (i.e., increases or enhances the absorption and / or bioavailability of the active ingredient through a mucous membrane).

[0201] Suitable examples include, but are not limited to, tetradecyl maltoside, sodium glycol cholate, tauroursodeoxycholic acid (TUDCA), lecithin, etc.; and chitosan (and salts), as well as surfactants such as benzalkonium chloride, sodium dodecyl sulfate, sodium dodecylate, polysorbate, laureth-9, oxytoxinol, sodium deoxycholate, polyarginine, etc. Preferably, the penetrating agent is tauroursodeoxycholic acid (TUDCA).

[0202] Penetrants may act through any mechanism, including, for example, increasing membrane fluidity, forming transient hydrophilic pores in epithelial cells, decreasing the viscosity of the mucus layer, or opening tight junctions. Some penetrants (e.g., bile salts and fusidic acid derivatives) can also inhibit enzyme activity in membranes, thereby improving the bioavailability of active ingredients.

[0203] Preferably, the penetrant is selected to meet one or more, and more preferably all, of the following general requirements:

[0204] [Table 5]

[0205] In one embodiment, the penetrant is selected to increase penetration (absorption and / or bioavailability of S-ketamine hydrochloride) without nasal irritation, hi another embodiment, the penetrant is selected to improve absorption and / or bioavailability of S-ketamine hydrochloride and further enhance uniform dosing effectiveness.

[0206] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising S-ketamine and water, wherein the pharmaceutical composition does not contain an antimicrobial preservative, and the pharmaceutical composition further contains a penetration enhancer, preferably TUDCA.

[0207] In another embodiment, the present disclosure is directed to a pharmaceutical composition comprising S-ketamine and water, wherein the pharmaceutical composition does not contain an antimicrobial preservative, and the pharmaceutical composition further comprises tauroursodeoxycholic acid (TUDCA), wherein the TUDCA is present at a concentration in the range of about 1.0 mg / mL to about 25.0 mg / mL, or any amount or range therein, preferably in the range of about 2.5 mg / mL to about 15 mg / mL, or any amount or range therein, preferably in the range of about 5 mg / mL to about 10 mg / mL, or any amount or range therein. In another embodiment, the present disclosure is directed to a pharmaceutical composition, wherein the TUDCA is present at a concentration of about 5 mg / mL. In another embodiment, the present disclosure is directed to a pharmaceutical composition, wherein the TUDCA is present at a concentration of about 10 mg / mL.

[0208] Pharmaceutical compositions for use herein may further contain one or more additional excipients, such as wetting agents, surfactant components, solubilizers, thickeners, colorants, antioxidant components, and the like.

[0209] Examples of suitable antioxidant components, when used, include, but are not limited to, one or more of the following: sulfites; ascorbic acid; ascorbate salts, such as sodium ascorbate, calcium ascorbate, or potassium ascorbate; ascorbyl palmitate; fumaric acid; ethylenediaminetetraacetic acid (EDTA) or its sodium or calcium salts; tocopherol; gallate salts, such as propyl gallate, octyl gallate, or dodecyl gallate; vitamin E; and mixtures thereof. The antioxidant component provides long-term stability to the liquid composition. The addition of the antioxidant component can help to enhance and ensure the stability of the composition, making the composition stable even after 6 months at 40°C. The suitable amount of the antioxidant component, when present, is about 0.01% to about 3% by weight, preferably about 0.05% to about 2% by weight, of the total weight of the composition.

[0210] Solubilizers and emulsifiers can be included to promote more uniform dispersion of active ingredients or other excipients that are not generally soluble in liquid carriers.Suitable examples of emulsifiers include, but are not limited to, gelatin, cholesterol, acacia, tragacanth, pectin, methylcellulose, carbomer, and mixtures thereof, if used.Suitable examples of solubilizers include polyethylene glycol, glycerin, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures thereof.

[0211] Preferably, the solubilizer comprises glycerin. The solubilizer or emulsifier is generally present in an amount sufficient to dissolve or disperse the active ingredient, i.e., S-ketamine, in the carrier. The typical amount of the solubilizer or emulsifier, if present, is about 1% to about 80% by weight, preferably about 20% to about 65% by weight, more preferably about 25% to about 55% by weight of the total weight of the composition.

[0212] Suitable tonicity agents, if used, include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, and mixtures thereof. If included, the suitable amount of tonicity agent is typically about 0.01% to about 15% by weight, more preferably about 0.3% to about 4% by weight, more preferably about 0.5% to about 3% by weight of the total weight of the composition.

[0213] For example, suspending or thickening agents may be added to the pharmaceutical composition to increase nasal retention time, suitable examples include, but are not limited to, hydroxypropylmethylcellulose, carmellose sodium, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salts, gellan gum, poloxamer, polyvinylpyrrolidone, xanthan gum, etc.

[0214] The following examples are provided to aid in the understanding of the present invention and are not intended, and should not be construed, as in any way limiting the invention described in the claims appended hereto.

[0215] [Table 6-1]

[0216] [Table 6-2]

[0217] Example 1 This was a multicenter, placebo-controlled, randomized, double-blind study in subjects with MDD who had an inadequate response to SSRI / SNRI treatment. Atticaplant was evaluated as an adjunctive therapy. Eligible subjects therefore maintained SSRI / SNRI treatment without modification throughout the study. At least 50% of recruited subjects had to be anhedonic (measured by a SHAPS total score ≥ 20).

[0218] A.Purpose The primary objective was to evaluate the efficacy of aticaplant compared with placebo when administered as adjunctive treatment in subjects with MDD partially responsive to SSRI / SNRI treatment, in reducing depressive symptoms as assessed by change from baseline in the MADRS in non-responders during the placebo run-in period.

[0219] Secondary objectives are to: To evaluate the efficacy of Aticaplant compared to placebo when administered as an adjunctive treatment in subjects with MDD who are partially responsive to SSRI / SNRI treatment, in reducing symptoms of depression as assessed by change from baseline in MADRS in both responders and non-responders during the placebo run-in period. ii. To investigate the overall safety and tolerability of adjunctive Aticaplant treatment in subjects with MDD when used in combination with an SSRI or SNRI. iii.To investigate the effects of Aticaplant versus placebo on depression-related anhedonia as assessed by SHAPS. iv. To investigate the effect of Aticaplant on symptoms of depression using the Clinical Global Impression-Severity (CGI-S), patient reported symptoms scale for Major Depressive Disorder (SMDDS) and Self-Evaluation of Treatment Experience (SATE). v. Using the HAM-A for symptoms of anxiety, and 6 To investigate the effect of Aticaplant on core symptoms of anxiety using subscales. vi. To evaluate the plasma PK of Atikaplant in subjects with MDD and investigate its relationship with efficacy and safety parameters.

[0220] Secondary exploration objectives are: To investigate the effects of Aticaplant on aspects of cognition and executive function using the CPFQ. ii. To explore mood-related biomarkers (including but not limited to growth factors, HPA axis markers, immune system activation, metabolic markers) and genetic / epigenetic variations that may be associated with clinical response, non-response, or safety and tolerability parameters of the Atticaplant.

[0221] B. Study Design For each subject, the study consisted of two phases: a screening phase of up to 5 weeks and a double-blind treatment phase lasting 11 weeks. See Figure 1.

[0222] Subjects with MDD who had initiated treatment with an approved SSRI / SNRI and had an inadequate or partial response to this treatment were screened. Assessments included the MINI, Antidepressant Treatment History Questionnaire (TRQ), and MADRS.

[0223] The treatment phase consisted of three periods: a concealed placebo run-in period, after which subjects were randomly assigned to 10 mg of aticaplant (two 5 mg capsules) or placebo, lasting 6 weeks. Each capsule contained aticaplant (5 mg), microcrystalline cellulose (94.95 mg) and magnesium stearate (0.05 mg) in a hard gelatin capsule. Subjects who completed the treatment period entered a withdrawal period and were treated with placebo for the remainder of the treatment phase. The total duration of each subject was approximately 16 weeks. There were 11 scheduled visits, including screening. The overall flow is shown in Figure 1.

[0224] Subjects were screened within 3-2 days prior to Day 1 to confirm eligibility according to the inclusion and exclusion criteria. Depressive symptoms were assessed using a structured interview guide for the MADRS.

[0225] Double-blind treatment phase The duration of the double-blind treatment phase was 11 weeks divided into three periods. Subjects received medication after completion of the Day 1 visit. The first dose was administered at home on Day 2. All medications were taken in the fasting state. At Visits 3, 4, and 5, subjects were re-randomized to blinded subjects for the placebo run-in period. During the double-blind phase, subjects visited the center for outpatient visits every 1-2 weeks. See Table 1.

[0226] [Table 7]

[0227] Run-in Period: Subjects who successfully completed the baseline examination visit at the clinical site / unit were treated with placebo for the entire duration of the run-in period.

[0228] Treatment Period: At the end of the run-in period, both placebo-initiated responders and placebo-initiated non-responders were randomized to receive either placebo or 10 mg Aticaplant in a 1:1 ratio for 6 weeks. Subjects remained blinded to the exact timing of randomization, response criteria, and medication assignment for each subject.

[0229] Weaning Period: Subjects who completed the double-blind treatment period before the end of week 11 entered a weaning period and were treated with placebo for the remainder of the treatment phase.

[0230] C. Dosage and Administration Atikaplant was provided as a 5 mg capsule. Placebo was provided as a matching capsule. All subjects received 2 capsules QD. Capsules were taken daily under fasting conditions (fasting at least 4 hours prior to dosing) with some water from day 2 through day 78. Drug was taken before breakfast. If a subject forgot to take a drug before breakfast, this was done before the next meal, at the latest the evening meal of the same day. If a subject remembered later than the evening meal, the dose for that day was omitted and the subject took the dose before breakfast the following day.

[0231] If Visit 11 was scheduled for 3 days later, subjects continued taking medication until Visit 11.

[0232] Capsules were swallowed whole without chewing, splitting, dissolving, or crushing. After taking the medication, subjects did not eat or drink anything for at least 30 minutes.

[0233] The first dose was taken in the fasting state on day 2 of the double-blind phase. 10mg Atika Plant: 2 capsules of 5mg Atika Plant Placebo: 2 placebo capsules.

[0234] The dose was adjusted to 5 mg QD as necessary based on the results of a blinded review of safety data. When a dose reduction was decided upon, this was only applicable to new subjects, and the drug doses were as follows: 5mg Atika Plant: 1 capsule of 5mg Atika Plant Placebo: 1 placebo capsule.

[0235] As used herein, the enhanced ITT analysis set (eITT) is defined as all enrolled lead-in placebo non-responders who are randomized to the treatment period, receive at least one dose of study drug during the treatment period, and have at least one post-baseline MADRS assessment during the treatment period. Similarly, the full ITT analysis set (fITT) is defined as all enrolled subjects who are randomized to the treatment period, receive at least one dose of study drug during the treatment period, and have at least one post-treatment baseline MADRS assessment during the treatment period.

[0236] D. Clinical Evaluation (i) Depression: Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity (CGI-S), Major Depressive Disorder Symptom Scale (SMDDS), and Self-Evaluation of Treatment Experience (SATE). (ii) Anhedonia: Snaith-Hamilton Pleasure Scale (SHAPS) (iii) Anxiety: Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A) and HAM-A6 (iv) Effects on cognition: Cognitive and Physical Functioning Questionnaire (CPFQ) (v) Safety Assessment: Standard safety assessments were performed including physical and neurological examination, vital signs, 12-lead ECG, clinical chemistry, hematology, and urinalysis. Based on observations of GI complaints in previous studies, a panel including PGI, PGII, G17, and Hp IgG was added to the clinical test panel to test for gastric mucosal status. (vi) Suicidal ideation: C-SSRS (vii) Exploratory: CPFQ (viii) Central sedative effect: Karolinska Sleepiness Scale (ix) Sexual dysfunction: ASEX

[0237] E. Patient Population Of the 184 subjects, 169 were randomized to the treatment period and included in the safety population, while 166 subjects were considered for the full ITT population. Of the 166 subjects in the full ITT population, 121 (73%) were induction placebo non-responders (enhanced ITT population), and the remaining 45 (27%) were induction placebo responders. Of the 121 subjects in the enriched population, 112 (92.6%) were white and 84 (69.4%) were female. The mean age was 41.6 years, ranging from 19 to 64 years. All subjects had anhedonia (defined as a SHAPS total score ≥ 20) at treatment baseline. High anhedonia levels (defined as a SHAPS total score ≥ 38) were observed in 43.8% of subjects. In general, the treatment groups were similar with respect to baseline characteristics. Subject demographics for the eITT and safety analyses are shown in Tables 2 and 3.

[0238] [Table 8]

[0239] [Table 9]

[0240] E. Efficacy Assessment At the end of the run-in period, subjects' response status was assessed according to double-blind response criteria based on the reduction in MADRS relative to the run-in baseline. Both run-in placebo responders and run-in placebo non-responders were randomly assigned in a 1:1 ratio to either Aticaplant or placebo in the treatment period. Randomization was based on run-in response status (non-responders: <30% reduction from baseline in MADRS total score at the end of the run-in period vs. responders: ≥30% reduction from baseline at the end of the run-in period) and the presence / absence of anhedonia (presence defined as a SHAPS total score ≥20).

[0241] Treatment Period: The study consisted of two periods: a screening phase of up to 5 weeks and a double-blind treatment phase of 11 weeks. The double-blind treatment phase of the study consisted of three periods. The first period was a 3-week placebo run-in, after which subjects entered either the treatment period in which they were randomly assigned to Atikaplant or a 6-week placebo extension period. Subjects who successfully completed the treatment period were treated with placebo for a 2-week withdrawal period, the third period. The total duration for each subject was approximately 16 weeks.

[0242] Primary Analysis Set for Efficacy: Efficacy analyses are based on the eITT set, defined as all enrolled lead-in placebo non-responders who were randomized in the treatment period, received at least one dose, and had at least one post-baseline MADRS assessment during the treatment period. The primary analysis set will be used for all efficacy endpoints.

[0243] Secondary Analysis Set for Efficacy: The secondary analysis set is the fITT set, defined as all enrolled subjects who were randomized in the treatment period, received at least one dose, and had at least one post-baseline MADRS assessment during the treatment period. The secondary analysis set will be used for all efficacy endpoints to examine effects in the general population, which may be useful for designing subsequent studies in the development program.

[0244] Analysis Set for Safety: The safety analysis is based on the full safety analysis set, defined as all enrolled subjects who received at least one dose of medication during the treatment period.

[0245] Efficacy endpoints were presented for both eITT and fITT.

[0246] Significance level: Analysis of the primary efficacy endpoint was performed at a significance level of 0.20 (one-sided). Analysis of efficacy endpoints was performed at a significance level of 0.20 (two-sided). No adjustment for multiple comparisons was made.

[0247] F. Results (i) Primary endpoint: Change from baseline in MADRS total score at week 6 of treatment in non-responders during the placebo run-in period

[0248] Enriched ITT analysis population The mean (SD) MADRS total score was 29.0 (4.61) with a range of 19 to 41. See Figure 2. The mean change from treatment baseline (SD) in MADRS total score at week 6 of treatment was -10.2 (8.44) for Aticaplant and -8.2 (8.53) for placebo. The observed effect size was 0.23. See Tables 4-6 and Figure 6.

[0249] [Table 10]

[0250] [Table 11]

[0251] [Table 12]

[0252] Based on the results of the MMRM model with subjects as random effects; country, treatment, time, and treatment-by-time interactions as factors; and baseline MADRS total score Aticaplant vs. placebo was found to have a significant positive efficacy signal at the one-sided 0.20 significance level. The estimated LS mean difference between Aticaplant and placebo at week 6 of treatment was -2.1, with an upper 80% one-sided CI limit of -1.09. The corresponding p-value was 0.044. The treatment effect was larger in the fITT population than in the eITT population: -3.1, with an upper 80% one-sided CI limit of -2.2 (p=0.002). The effect sizes were 0.36 and 0.23, respectively. See Figures 2 and 3.

[0253] Complete ITT Analysis Set The mean (SD) baseline MADRS total score at treatment baseline was 25.3 (7.86) with a range of 0 to 41. See Figures 7A and 7B. The mean change from treatment baseline in MADRS total score at treatment week 6 for fITT was smaller than for eITT: -9.7 (8.02) for Aticaplant and -6.6 (8.57) for placebo. The observed effect size was 0.36. These results indicate a statistical advantage over placebo with a persistence of effect with the largest difference seen at week 6. See Table 7.

[0254] [Table 13]

[0255] A significant effect for Atikaplant vs. placebo in the fITT population was also detected. The estimated LS mean difference between Atikaplant and placebo at week 6 of treatment was -3.1, with an upper 80% one-sided CI of -2.21. The corresponding p-value was 0.002. See Tables 8-9 and 3.

[0256] [Table 14]

[0257] [Table 15]

[0258] Impact of COVID-19 on primary efficacy assessment A supplemental analysis was performed on all data collected before March 15, 2020 (the estimated date of COVID-19 lockdown in most countries participating in the trial) using the same MMRM model as described for the primary analysis. Seventeen percent of subjects in the fITT and 19% in the eITT population had at least one MADRS assessment excluded from the model due to COVID-19 impact. Results of the analysis supported the findings of the primary efficacy analysis in both the eITT and fITT populations. The LS mean difference estimate was -3.0 (upper limit of 80% one-sided CI -1.88) for eITT and -3.4 (upper limit of 80% one-sided CI -2.51) for fITT.

[0259] (ii) Secondary Endpoints MADRS remission rate over the treatment period At week 6 of treatment, the percentage of subjects with MADRS remission (MADRS total score ≦10) in the eITT population was 16.9% for Atika plant and 16.9% for placebo. At week 6 of treatment, the remission rate in the fITT population was 31.2% for Atika plant and 22.2% for placebo. No significant treatment differences were detected at week 6 of treatment for both populations (eITT and fITT) using a chi-square test (two-tailed p=0.999 and p=0.203, respectively). See Figures 8 and 9.

[0260] MADRS response rate (at least 30% improvement) over the treatment period The proportion of subjects with a ≥ 30% improvement in MADRS total score at week 6 in the eITT population was 57.6% for Atikaplant and 45.8% for placebo. The response rate at week 6 in the fITT population was 61.8% for Atikaplant and 44.4% for placebo. For both populations, the treatment difference at week 6 was significant at the 20% two-sided significance level (chi-square test: p = 0.197 for eITT and p = 0.029 for fITT).

[0261] MADRS response rate (at least 50% improvement) over the treatment period The proportion of subjects with a ≥ 50% improvement in MADRS total score at week 6 in the eITT population was 35.6% for the Atika plant and 22.0% for the placebo group. The response rate at week 6 in the fITT population was 38.2% for the Atika plant and 23.5% for the placebo group. For both populations, the treatment difference at week 6 was significant at the 20% two-sided significance level (chi-square test: p = 0.104 for eITT and p = 0.046 for fITT). See Table 10 and Figures 10-13.

[0262] [Table 16]

[0263] Change in SHAPS total score from baseline to week 6 of treatment Enriched ITT analysis population In the eITT population, a larger difference was observed between acicaplant and placebo at week 6 of treatment in the subgroup of subjects with high anhedonia levels (baseline SHAPS total score ≥ 38) than in subjects with low anhedonia levels (baseline SHAPS total score ≤ 20 < 38). The effect sizes were 0.38 and 0.11, respectively.

[0264] The mean (SD) SHAPS total score at treatment baseline was 36.6 (5.45) with a range of 20 to 50. The mean change from treatment baseline (SD) in SHAPS total score at week 6 of treatment was -4.6 (6.23) for Aticaplant and -4.2 (5.04) for placebo. The observed effect size was 0.07. See Table 11 and Figures 14 and 23.

[0265] [Table 17]

[0266] The change in SHAPS total score was analyzed using the same MMRM model used for the MADRS total score. The estimated LS mean difference with 80% two-sided CI between Aticaplant and placebo at week 6 of treatment was -0.7 [-1.81, 0.41]. See Figure 4 and Tables 12 and 13 and Figure 15. The corresponding p-value was 0.419.

[0267] [Table 18]

[0268] [Table 19]

[0269] The estimated LS mean difference with 80% two-sided CI between Aticaplant and placebo at week 6 of treatment was -0.8 [-1.79, 0.10]. The corresponding p-value was 0.250. See Figures 4 and 5.

[0270] Complete ITT Analysis Set A similar trend was observed in the fITT population, with the difference being larger than that observed in the eITT population. The effect sizes were 0.51 and 0.29, respectively. The mean (SD) baseline SHAPS total score was 35.6 (5.67) with a range of 14 to 50. The mean change from treatment baseline in SHAPS total score at treatment week 6 for the fITT population was similar to the change in the eITT: -4.7 (5.91) for Atticaplant and -4.2 (4.98) for placebo. The observed effect size was 0.08. See Table 14.

[0271] [Table 20]

[0272] Change in MADRS total score from baseline to week 6 of treatment by baseline anhedonia level Enriched ITT analysis population In the subgroup of subjects with high anhedonia levels (SHAPS total score ≥ 38) at treatment baseline, n = 53, a larger difference between Aticaplant and placebo was observed at week 6 of treatment than in subjects with low anhedonia levels (baseline SHAPS total score ≤ 20 < 38), n = 65: -3.4 with 90% two-sided CI of [-7.5, 0.7] and -0.9 with 90% two-sided CI of [-4.2, 2.5], respectively (Table 15). The observed effect sizes were 0.38 and 0.11, respectively.

[0273] [Table 21]

[0274] Complete ITT Analysis Set A similar trend was observed in the fITT population. The difference was larger in magnitude compared to the eITT population: -4.6 with a 90% 2-sided CI of [-8.4, -0.8] for subjects with high anhedonia levels (n=63) and -2.3 with a 90% 2-sided CI of [-5.0, 0.4] for subjects with low anhedonia levels (n=94). See Table 16. The observed effect sizes were 0.51 and 0.29, respectively.

[0275] [Table 22]

[0276] The data indicate that segmentation into high vs. low anhedonia was beneficial for treating MDD, i.e., the treatment effect for the Atika plant was higher. Furthermore, the placebo response was lower in patients with high anhedonia compared to low anhedonia.

[0277] Change from treatment baseline in CGI-S total score upon treatment

[0278] [Table 23]

[0279] Change from baseline in SMDDS total score at week 6 of treatment

[0280] [Table 24]

[0281] Number of subjects with SATE score at 6 weeks of treatment

[0282] [Table 25]

[0283] Change from baseline in HAM-A6 total score at week 6 of treatment

[0284] [Table 26]

[0285] These data show greater improvements in HAMA6 scores in Atticaplant treated patients versus placebo.

[0286] Change from treatment baseline in structured interview guide for SIGH-A scores at week 6 of treatment

[0287] [Table 27]

[0288] Maximum plasma concentration of Atikaplant (C max ) C maxis defined as the maximum plasma concentration of Aticaplant. The eITT population included all enrolled lead-in placebo non-responders who were randomized into the treatment period, received at least one dose of study drug, and had at least one post-baseline MADRS assessment during the treatment period. Here, "N" (number of subjects analyzed) includes the number of subjects evaluable for this endpoint. Here, "n" (number analyzed) includes all subjects evaluable for a particular time point category.

[0289] [Table 28]

[0290] (iii) Safety Endpoints Overall, 40 / 85 (47.1%) subjects in the Atticaplant group and 30 / 84 (35.7%) in the placebo group in the full safety analysis set experienced at least one TEAE during the treatment period. See Table 23.

[0291] [Table 29]

[0292] The most common TEAEs during treatment were headache (experienced by 10 / 85 subjects in the Atika Plant group - 11.8% and 6 / 84 subjects in the placebo group - 7.1%) and diarrhea (experienced by 7 / 85 subjects in the Atika Plant group - 8.2% and 2 / 84 subjects in the placebo group - 2.4%). See Table 24.

[0293] [Table 30]

[0294] A total of two subjects discontinued during the treatment period due to treatment-emergent adverse events: one subject in the Aticaplant 10 group due to diarrhea, nausea, vomiting, and headache, and one subject in the placebo group due to acute gallstone cholecystitis.

[0295] Overall, 17 of 169 subjects experienced TEAEs of special interest during the treatment period: 13 of 85 (15.3%) in the Atikaplant group and 4 of 84 (4.8%) in the placebo group. The most common treatment-emergent adverse events during the treatment phase were headache and diarrhea. The most common TEAEs of special interest during the treatment period were diarrhea and pruritus (experienced by 5 / 85 subjects - 5.9% in the Atikaplant group and 0 / 84 subjects in the placebo group). In addition, 1 patient (1.19%) in the placebo group experienced acute cholecystitis compared to 0 patients who received Atikaplant. See Table 25.

[0296] [Table 31]

[0297] Two serious adverse events occurred: one subject in the placebo group experienced acute gallstone cholecystitis during the treatment period, and the other subject experienced suicidal ideation during the run-in period. Both subjects discontinued due to these AEs.

[0298] No deaths were reported.

[0299] (iv) Anhedonia analysis Patients in the larger fITT group maintained baseline levels of depression and anhedonia severity consistent with the eITT group. See Tables 26-28.

[0300] [Table 32]

[0301] The results show that the treatment effect was greater in patients with more anhedonia at baseline. See Figure 16.

[0302] [Table 33]

[0303] [Table 34]

[0304] The results show that the treatment effect is greater in patients with more anhedonia at baseline. See Figures 17A and 17B. In Figure 17A, i.e., in the high anhedonia group, the placebo + oral antidepressant group shows less placebo response compared to the low anhedonia group in Figure 17B. Similarly, the treatment effect of the Aticaplant + oral antidepressant group is higher in the high anhedonia group compared to the low anhedonia group. Overall, the effect size is greater in the high anhedonia group at all single time points (from week 1 onwards). The LSMD in the high anhedonia group is more than twice that of the low anhedonia group at week 6. Furthermore, looking at symptom levels, there is a greater improvement in anhedonia and dysphoria-related items in the subgroups with high vs. low anhedonia. See Figure 18.

[0305] (v) Weight change At the induction baseline, the mean weight of subjects in the placebo group was 76.17 kg compared to 78.66 kg in the Atika Plant group. After 6 weeks in the double-blind treatment phase, the mean weight in the placebo group was 75.75 kg compared to 78.57 kg in the Atika Plant group. This indicates that the weight of both groups remained relatively stable over the 6-week double-blind treatment period. This is unexpected, as other adjunctive treatments for MDD result in mean weight gain. Thase M,et al.J Clin Psych.2015:76(9),1224-1231,Thase,J Clin Psych.2015,76(9):1232-1240;El Khalili,Int J Neuropsychopharmacol.2010,13,917-932, Marcus,J.Clin.Psychopharmacol.2008,28:156-165, Berman,J.Clin.Psychiatry 2007;68:843-853;Berman,American College of Neuropsychopharmacology,2008,Annual Meeting Abstracts(Scottsdale,Ariz,Dec. 7-11, 2008). Nashville, Tenn, ACNP, 2008, Earley, American College of Neuropsychopharmacology, 2007, Annual Meeting Abstracts (Boca Raton, Fla., Dec 9-13, 2007. Nashville, TN, ACNP, 2007. See Table 29.

[0306] [Table 35]

[0307] (vi) Completion rate Patients who passed the screening phase entered the run-in phase followed by the double-blind phase. Patients who responded to the placebo during the run-in phase were classified as non-responders. Patients who did not respond to the placebo were classified as non-responders. The double-blind treatment phase then continued for an additional 6 weeks, after which patients entered a withdrawal period.

[0308] Of the 121 subjects in the enrichment population (60 in the Atika Plant and 61 in the placebo group), 117 (96.7%) completed the study. The overall completion rate for the full ITT analysis set is 95%. This contrasts with a completion rate of approximately 85% for the adjunctive aripiprazole study (Pae, CNS Drugs, 2011;25,109-127) and 45-62% for adjunctive quetiapine (El Khalili, cited above). A total of four subjects (3.3%) discontinued the study: two subjects in the placebo and two subjects in the Atika Plant treatment group. See Tables 30 and 31.

[0309] [Table 36]

[0310] [Table 37]

[0311] (vii) Sexual function Impaired sexual function is a common side effect of antidepressant therapy and can be very disruptive to patients and their sexual partners. Major depression itself is associated with increased sexual dysfunction, and many pharmacological treatments are known to further worsen sexual function. In a large survey of almost 5000 patients in France, the prevalence of sexual dysfunction was estimated to be 65% in untreated patients with MDD. The prevalence of sexual dysfunction increased to 71% for patients treated with antidepressant therapy.

[0312] Sexual pleasure is an important component of hedonism. The brain reward circuit is controlled by several areas: the nucleus accumbens, the ventral tegmental area and the amygdala. It is hypothesized that treatment with kappa opioid receptors may restore normal homeostatic balance in patients with overactivation. Treatment with Aticaplant may improve symptoms of anhedonia. Other symptoms related to the reward circuit include lack of sexual pleasure, lack of interest and lack of enjoyment.

[0313] Patients had sexual function measured using the ASEX, a standard, familiar rating scale. See Table 32.

[0314] [Table 38]

[0315] The mean change from treatment baseline (SD) in ASEX total score by week 6 was -1.5 (4.02) points for Atika Plant compared to -0.7 (2.98) points for placebo. Lower scores in ASEX indicate improvement. Score reduction at week 6 was greater in the Atika Plant group compared to placebo. This is unexpected, since adjunctive treatment with other drugs is expected to worsen sexual function, i.e., increase ASEX score over time. See Figure 19.

[0316] Patients who received Aticaplant had significant improvements in sexual function. Examination of individual item-level changes was also performed and revealed that the greatest changes were seen in items related to consummatory pleasure: orgasm satisfaction, orgasm attained, and vaginal lubrication / erection. Most of the improvement is seen in items 3, 4, and 5 in Figure 20.

[0317] (viii) Onset of Effect The onset of effect for Atikaplant can be estimated from the study. Figure 7B shows the least squares mean change from baseline. A significant treatment effect in favor of Atikaplant was seen as early as week 3. At this time point, Atikaplant showed a statistically superior effect compared to placebo.

[0318] Example 2: Single-dose Aticaplant as adjunctive antidepressant therapy Study Design: A 6-week, multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy, safety, and tolerability of Aticaplant in adult and elderly subjects (18-74 years) with MDD with prominent anhedonia (MDD ANH+) and who had an inadequate response to SSRIs or serotonin and SNRIs in the current depressive episode. See Figure 21.

[0319] For all subjects, the study will consist of three phases: an eligibility screening phase (up to 4 weeks prior to administration of the first dose), a 6-week double-blind treatment phase, and a 1-2 week follow-up. Subjects who complete the double-blind phase may enter an open-label long-term safety study.

[0320] Sample size and randomization: Approximately 544 subjects with MDD with prominent anhedonia (MDD ANH+) and MDD without prominent anhedonia (MDD ANH-) will be randomized in a 1:1 ratio to adjunctive placebo or acicaplant to achieve a minimum of 314 adult subjects meeting predefined criteria for MDD ANH+ eligible for inclusion in the primary analysis. Randomization will be stratified by study center, age group (adult [<65 years], elderly [>=65 years]), baseline anhedonia, and baseline MADRS total score. All subjects will continue their baseline antidepressant (SSRI / SNRI) for the entire study.

[0321] Dose and Administration All eligible subjects will receive aticaplant or placebo in addition to their baseline SSRI / SNRI. Study drug will be taken daily.

[0322] Inclusion Criteria:

[0323] [Table 39]

[0324] Exclusion criteria:

[0325] [Table 40-1]

[0326] [Table 40-2]

[0327] A. Efficacy Objectives and Endpoints Assessment of primary and secondary (primary and other) endpoints will be performed on the FAS, which includes adult (non-elderly) subjects with MDD ANH+ who have taken at least one dose of study medication.

[0328] Primary: To evaluate the efficacy of Aticaplant compared to placebo as adjunctive therapy to antidepressants (SSRI or SNRI) in improving depressive symptoms in adult subjects with MDD ANH+ and an inadequate response to current antidepressants, as assessed by change from baseline in MADRS total score from Day 1 (pre-randomization) to the end of the 6-week double-blind treatment phase (Day 43): - Change from baseline to week 43 in MADRS total score.

[0329] Primary Secondary: To evaluate the efficacy of Aticaplant compared to placebo in adult subjects with MDD ANH+ as adjunctive therapy to antidepressants on patient-reported assessment of anhedonia outcomes: - Change from baseline to day 43 in the Dimensional Anhedonia Rating Scale (DARS) total score.

[0330] Other Secondary: To evaluate the efficacy of Aticaplant compared to placebo in adult subjects with MDD ANH+ as an adjunctive treatment for: Proportion of responders at Day 43 (≥ 50% reduction in MADRS total score). Proportion of subjects with remission of depressive symptoms, defined as a MADRS total score ≦12 at Day 43. Change in MADRS 6 from baseline to day 43 - Change in PHQ-9 total score from baseline to week 43. - Change in SHAPS total score from baseline to week 43. - Change in symptoms of anxiety using GAD-7 from baseline to day 43.

[0331] Exploratory: To evaluate the efficacy of Aticaplant as an adjunctive treatment compared to placebo in adult subjects with MDD ANH+ and all MDD subjects (adults and elderly subjects with MDD ANH+ and MDD ANH-) on: -Change from baseline over time in MADRS total score. Change from baseline in MADRS anhedonia item factor scores over time. -Changes from baseline over time in patient-reported outcomes of anhedonia (SHAPS, DARS). Change from baseline in PHQ-9 total score over time. Change from baseline to Day 43 in health-related quality of life and health status as assessed by the EQ-5D-5L questionnaire. - Change from baseline to week 43 in SDS total score. Change from baseline in CGI-S scores over time. Change from baseline over time in anxiety symptoms using the GAD-7. Change from baseline over time in depressive symptoms using the PGI-S. -Change from baseline to Day 43 in patient-reported sexual function using ASEX.

[0332] To evaluate the efficacy of Aticaplant compared to placebo in adult subjects with MDD ANH- as an adjunctive treatment for: -Change from baseline over time in MADRS total score. -Change from baseline over time in DARS total score.

[0333] Safety Objectives (All): The following safety endpoints will be evaluated separately for adult and geriatric subjects. The safety analysis set for each age group will include all randomized subjects who received at least one dose of study drug. ·AE includes AESI. An AE may be any untoward or unintended sign (e.g., laboratory abnormality), symptom, or disease that is temporally related to the use of a medicinal product (investigational or non-investigational medicinal product), whether or not it is causally related to the medicinal product (investigational or non-investigational medicinal product). A TEAE was an AE that occurred during the treatment phase that worsened from baseline. The full safety analysis set included all enrolled subjects who received at least one dose of the investigational product during the treatment period. Vital signs ECG, laboratory data ·Weight / BMI -Assessment of suicidality using the C-SSRS Evaluation of withdrawal symptoms using PWC-20

[0334] B. Concomitant and Prohibited Therapies Background Therapy: All subjects will continue their baseline antidepressant (SSRI / SNRI) for the entire study period. The following antidepressants are permitted: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, and desvenlafaxine. Subjects will continue on only one of these permitted antidepressants (i.e., monotherapy) during the study, at an appropriate and tolerated dose. No changes in antidepressant or dose will be permitted from screening to the end of the study.

[0335] Prohibited Therapies: Subjects must not use the following medications or dietary supplements before or during the study, as indicated, except to treat AEs or breakthrough symptoms, preferably after the EOT visit: -MAOIs within 4 weeks prior to screening through the first follow-up visit. Antipsychotics from at least 14 days prior to Day 1 until the first follow-up visit. Benzodiazepines, non-benzodiazepine hypnotics (e.g., hypnotics including, but not limited to, zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant, and ramelteon) or dietary supplements (from at least 7 days prior to Day 1 until the first follow-up visit), sedating antihistamines including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine), and melatonin / agomelatine. Subjects taking benzodiazepines and / or non-benzodiazepine hypnotics during the screening phase may continue these medications (at doses up to the equivalent of 6 mg / day lorazepam) during the double-blind treatment phase. Dose escalation above the equivalent of 6 mg / day lorazepam or new benzodiazepine medications will not be permitted during the double-blind treatment phase. Non-SSRI / SNRI antidepressants (e.g., doxepin, trazodone, mirtazapine, bupropion, tricyclic antidepressants, agomelatine, and SAMe) from at least 7 days prior to Day 1 until the first follow-up visit. Any form of new psychotherapy or change in current psychotherapy is prohibited during the screening and double-blind phases. Opiates and mood stabilizers (e.g., lithium and anticonvulsants) from at least 7 days prior to Day 1 until the first follow-up visit. · Stimulants (e.g., dexamphetamine, methylphenidate, dexmethylphenidate), oral systemic steroids, and appetite suppressants (ephedrine), and isoxsuprine for at least 7 days prior to Day 1 until EOT. Magnetic and Electrical Stimulation Therapies: Electrical shock, vagus nerve stimulation, deep brain stimulation, any type of TMS, or DCS or electrical stimulation from screening through the end-of-study visit. The use of TMS or DCS or electrical stimulation prior to screening is not exclusive. T3, thyroid hormones or other thyroid function supplements prescribed for depression. These medications are permitted if given to control an existing thyroid disease / disorder. Ketamine or esketamine within 5 years prior to and during the study (maximum of 2 doses in the lifetime prior to screening is permitted). Psychedelics (e.g. psilocybin). Memantine. -Other investigational drugs within 30 days prior to and during the study.

[0336] Example 3: A randomized, double-blind, multicenter, placebo-controlled study to evaluate the efficacy, safety, and tolerability of fixed doses of Aticaplant 5 mg and 10 mg as adjunctive therapy in adult and geriatric subjects with MDD with prominent anhedonia and inadequate response to current antidepressant therapy Study Design: An 8-week, multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy, safety, and tolerability of Aticaplant in adult and elderly subjects (18-74 years) with MDD with prominent anhedonia and who have had an inadequate response to SSRIs or SNRIs in the current depressive episode. See Figure 22.

[0337] For all subjects, the study consisted of three phases: Eligibility screening phase (up to 4 weeks prior to administration of the first dose), An 8-week double-blind treatment phase, · and a 1-2 week follow-up phase.

[0338] Approximately 624 subjects (randomized in a 2:1:1 ratio to placebo, 5 mg acetaminophen, and 10 mg acetaminophen) will be enrolled in the study with the goal of achieving a minimum of 556 adult subjects with MDD with prominent anhedonia and approximately 68 elderly subjects (>= 65 years) with MDD with prominent anhedonia.

[0339] Subjects who complete the double-blind treatment phase may enter an open-label long-term safety study.

[0340] Sample size and randomization: Approximately 624 adult (<65 years) and elderly (>65 years) subjects with MDD with prominent anhedonia will be randomized in a 2:1:1 ratio to adjunctive placebo, 5 mg ataticaplant, or 10 mg ataticaplant to achieve a minimum of 556 adult subjects who meet the predefined criteria for MDD with prominent anhedonia eligible for inclusion in the primary efficacy analysis set. Randomization will be stratified by study center, age group (adult, elderly), and baseline MADRS total score. All subjects will continue their baseline antidepressant (SSRI / SNRI) for the entire study.

[0341] Dose and Administration: All eligible subjects will receive Aticaplant 5 mg, Aticaplant 10 mg, or placebo in addition to their baseline SSRI / SNRI, which will be continued for the entire study. Study medication will be taken daily.

[0342] Inclusion Criteria:

[0343] [Table 41]

[0344] Exclusion criteria:

[0345] [Table 42-1]

[0346] [Table 42-2]

[0347] A. Efficacy Objectives and Endpoints Assessment of the primary and secondary (primary and other) endpoints will be performed on the full analysis set (FAS), which includes adult (non-elderly) subjects with MDD with significant anhedonia who have taken at least one dose of study medication.

[0348] Primary: To evaluate the efficacy of two fixed doses of Aticaplant (5 mg and 10 mg) compared with placebo as adjunctive therapy to antidepressants (SSRI or SNRI) in improving depressive symptoms in adult subjects (18-64 years) with MDD with prominent anhedonia and inadequate response to current antidepressants. - Change from baseline to week 43 in MADRS total score.

[0349] Primary Secondary: To evaluate the efficacy of Aticaplant 10 mg compared with placebo as adjunctive therapy to antidepressants on patient-reported assessments of anhedonia outcomes in adult subjects with MDD with prominent anhedonia: - Change from baseline to day 43 in the Dimensional Anhedonia Rating Scale (DARS) total score.

[0350] Other secondary: To evaluate the efficacy of Aticaplant compared to placebo as adjunctive therapy to antidepressants (SSRI or SNRI) in adult subjects with MDD with prominent anhedonia. Proportion of responders (≥ 50% reduction in MADRS total score) at Day 43 and Day 57. Proportion of subjects with remission of depressive symptoms, defined as a MADRS total score ≦12 at Day 43 and Day 57. Changes from baseline to days 43 and 57 in MADRS-6 Change from baseline to Day 43 and Day 57 in the Patient Health Questionnaire, 9-item (PHQ-9) total score.

[0351] Exploratory: To evaluate the efficacy of Aticaplant compared to placebo in adult subjects with MDD with prominent anhedonia as an adjunctive treatment: -Change from baseline over time in MADRS total score. Change from baseline in MADRS anhedonia item factor scores over time. -Changes from baseline over time in patient-reported outcomes of anhedonia (SHAPS, DARS). Change from baseline in PHQ-9 total score over time. Change from baseline to Day 43 in health-related quality of life and health status as assessed by the EQ-5D-5L questionnaire. - Change from baseline to Day 43 in Sheehan Disability Scale (SDS) total score. Change from baseline in CGI-S scores over time. Change from baseline over time in anxiety symptoms using the GAD-7. Change from baseline over time in depressive symptoms using the PGI-S. -Change from baseline to Day 43 in patient-reported sexual function using ASEX.

[0352] Safety Objectives (All): The following safety endpoints will be evaluated separately for adult and geriatric subjects. The safety analysis set for each age group will include all randomized subjects who received at least one dose of study drug. AE includes AESI Vital signs ECG Test values ·Weight / BMI -Assessment of suicidality using the C-SSRS Evaluation of withdrawal symptoms using PWC-20

[0353] Other objectives (exploratory): To identify diagnostic biomarkers and investigate changes in MDD-related biomarkers in relation to clinical response to depression and anhedonia during monotherapy with Aticaplant. To identify genetic and other factors that may affect the pharmacokinetics (PK), safety, or tolerability of Atikaplant.

[0354] B. Concomitant and Prohibited Therapies Background Therapy: All subjects will continue their baseline antidepressant (SSRI / SNRI) for the entire study period. The following antidepressants are permitted: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, and desvenlafaxine. Subjects will continue on only one of these permitted antidepressants (i.e., monotherapy) during the study, at an appropriate and tolerated dose. No changes in antidepressant or dose will be permitted from screening to the end of the study.

[0355] Prohibited Therapies: Subjects must not use the following medications or dietary supplements before or during the study, as indicated, except to treat AEs or breakthrough symptoms, preferably after the EOT visit: -MAOIs within 4 weeks prior to screening through the first follow-up visit. Antipsychotics from at least 14 days prior to Day 1 until the first follow-up visit. Benzodiazepines, non-benzodiazepine hypnotics (e.g., hypnotics including, but not limited to, zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant, and ramelteon) or dietary supplements (from at least 7 days prior to Day 1 until the first follow-up visit), sedative antihistamines including over-the-counter hypnotics (e.g., diphenhydramine, doxylamine, and hydroxyzine), and melatonin. Subjects taking benzodiazepine and / or non-benzodiazepine hypnotics during the screening phase may continue these medications (at doses up to and including the 6 mg / day dose of lorazepam). Dose escalation beyond the equivalent of 6 mg / day lorazepam, or new benzodiazepine medications, will not be permitted during the double-blind treatment phase. Non-SSRI / SNRI antidepressants (e.g., doxepin, trazodone, mirtazapine, bupropion, tricyclic antidepressants, agomelatine, and SAMe) from at least 7 days prior to Day 1 until the first follow-up visit. During the screening and double-blind phases of the study, any form of new psychotherapy or change in current psychotherapy is prohibited. Opiates and mood stabilizers (e.g., lithium and anticonvulsants) from at least 7 days prior to Day 1 until the first follow-up visit. · Stimulants (e.g., dexamphetamine, methylphenidate, dexmethylphenidate), oral systemic steroids, and appetite suppressants (ephedrine), and isoxsuprine for at least 7 days prior to Day 1 until EOT. Magnetic and Electrical Stimulation Therapies: Electrical shock, vagus nerve stimulation, deep brain stimulation, any type of TMS, or DCS or electrical stimulation from screening through the end-of-study visit. The use of TMS or DCS or electrical stimulation prior to screening is not exclusive. T3, thyroid hormones or other thyroid function supplements prescribed for depression. These medications are permitted if given to control an existing thyroid disease / disorder. Ketamine or esketamine within 5 years prior to and during the study (maximum of 2 doses in the lifetime prior to screening is permitted). Psychedelics (e.g. psilocybin). Memantine. -Other investigational drugs within 30 days prior to and during the study.

[0356] Example 4: Biomarker Assays Venous blood samples were obtained from patients and healthy control subjects from a multicenter, placebo-controlled, randomized, double-blind study in subjects with MDD who showed an inadequate response to SSRI / SNRI treatment as described in Example 1. Serum or plasma was prepared from the venous blood samples. Human CRP and IL-6-R measurements were performed in serum using an MSD Sector 6000 with kits #K151STD and K151ALC (MesoScale Discovery, Rockville, MD). Human TNFα was quantified in serum using a Simoa HD-1 analyzer with kit #143 (Quanterix, Lexington, MA). Human dynorphin was assayed in plasma using a SpectraMax M plate reader (Molecular devices, San Jose, CA) with kit #CSB-E09128h (Cusabio, Wuhan, China). All measurements were performed according to the kit manufacturer's recommendations.

[0357] As used in the following biomarker assay analyses, treatment (TRT) refers to treatment with SSRI / SNRI + atticaplant and placebo (PBO) refers to treatment with SSRI / SNRI + placebo.

[0358] The following biomarker signatures were used: Treatment outcome: change in clinical scales at the end of the dual period. Negative values ​​indicate improvement in depression levels relative to baseline levels. The more negative the change, the greater the improvement.

[0359] Sig Pos : Patients who meet criteria defined by a biomarker signature and / or clinical scale.

[0360] 3MM: Inflammatory biomarker signature with a positive status defined by CRP>3mg / L and (TNFα>4pg / mL or sIL6R>25ng / mL).

[0361] 4MM: Inflammatory biomarker signature with positive status defined by 3MM with high dynorphin (δ1) or intermediate dynorphin (δ2) subtype, specifically DYN>δ1 pg / mL or (DYN>δ2 pg / mL and CRP>3 mg / L and (TNFα>4 pg / mL or sIL6R>25 ng / mL). In certain embodiments, the 4MM DYN cutoffs are as follows: Dyn>50 OR (3MM and Dyn>8); Dyn>24 OR (3MM and Dyn>8), or Dyn>11.4 and 3MM.

[0362] TE Sig Pos Treatment effect in signature positive group:Sig Pos In groups (mean MADRS change in placebo - mean MADRS change in treatment).

[0363] TE Sig Neg :Treatment effect in signature-negative group.

[0364] Sig Adv: Signature dominance (interaction) difference in TE between signature groups: Sig Adv = TE Sig Pos -TE Sig Neg .

[0365] The effect of biomarker signatures on patients' response to treatment is summarized in graphical form using two panel box plots in FIG. 25. The left panel of FIG. 25 shows treatment outcomes relative to baseline in the biomarker signature positive group, defined herein as subjects whose biomarker profile fits the three-marker model (3MM) (21% of MDD). The right panel of FIG. 25 shows treatment outcomes in the biomarker signature negative group using Tukey box plots, in addition to individual patient outcomes marked by circle points. Red represents placebo and cyan represents Aticaplant. The rectangular box spanning the diamond and error bars represent the mean and 95% confidence interval (CI) of treatment outcomes by treatment group and biomarker signature status. In the signature positive group, the treatment outcome (difference in mean treatment outcomes between treatment groups) was 6.29 MADRS points (one-sided p=0.07, effect size=0.75). Meanwhile, in the signature-negative group, the treatment effect was 1.59 MADRS points. In other words, subjects who are biomarker signature positive improve an additional 4.7 points (6.29 to 4.7) over placebo when treated with Aticaplant compared to subjects who are biomarker signature negative. This signature advantage of 4.7 MADRS points represents the interaction between biomarker signature status and treatment effect. Treatment effect, signature advantage, and corresponding p-values ​​are assessed using a linear regression model for treatment outcome with independent variables for treatment, biomarker signature status, and their interactions. All p-values ​​are one-sided. Significance is defined as a nominal one-sided p-value <0.05.

[0366] Figures 26A-26D show the results of patient subtyping using a biomarker signature consisting of dynorphin levels only, i.e., DYN>δpg / mL. Biomarker signature effects are shown across a range of values ​​for δ from 6.2pg / mL to 116.2pg / mL. At each value tested, the treatment effect and signature dominance in the biomarker signature positive group are calculated and graphed in Figure 26A. The percentages shown along the top of the graphs indicate the proportion of subjects that are biomarker signature positive at a particular threshold. Both treatment effect (SigPos:PBO-TRT) and signature dominance (SigPos.DIFF-SigNeg.DIFF) increase with increasing δ, peaking around δ=19.9pg / mL. Figures 26B and 26C show the signature effect at δ levels of 19.9 and 30pg / mL, respectively. However, at high levels of dynorphin (FIG. 26D), the signature effect was more variable.

[0367] Figures 27A-27D summarize the results of patient subtyping using a biomarker signature using a combination of high dynorphin and 3MM subtypes, specifically DYN>δpg / mL or CRP>3mg / L and (TNFα>4pg / mL or sIL6R>25ng / mL). Similar to Figures 26A-26D, the effect of the biomarker signature is evaluated at a range of dynorphin cut points (δ). Similar to the signature with dynorphin alone, the treatment effect increases with increasing δ, but the interaction effect is considerably more pronounced due to the mean Atticaplant response being worse than placebo for biomarker signature negative patients (Figure 26B). More importantly, the effect of the biomarker signature is more stable at higher dynorphin cut points (Figures 27C and 27D), making this biomarker signature a more reliable identifier of patients most likely to benefit from treatment with Atticaplant as an adjunctive treatment compared to SOC alone. Targeting both the DYN high and 3MM subtypes results in a 3-8 point signature advantage in over 60% of patients.

[0368] Figures 28A and 28B show the effect of the biomarker signature to capture subjects who are both 3MM positive and have high dynorphin: DYN>δpg / mL and CRP>3mg / L and (TNFα>4pg / mL or sIL6R>25ng / mL). A very large treatment effect was observed in biomarker signature positive patients and a large signature advantage over a wide range of dynorphin levels (Figure 28B, corresponding to δ=11.5). This significant improvement by Atika plant in patients with both high dynorphin and high inflammation suggests that the two identified subtypes reflect different pathologies that are both responsive to Atika plant.

[0369] Figures 29A-29C summarize the results of patient subtyping using biomarker signatures using a combination of high dynorphin (δ1) or 3MM with intermediate dynorphin (δ2) subtypes, specifically, DYN>δ1pg / mL or (DYN>δ2pg / mL and CRP>3mg / L and (TNFα>4pg / mL or sIL6R>25ng / mL). The effect of the biomarker signatures is evaluated over a range of dynorphin cut points (δ) for δ1, while the δ2 ​​cut point in combination with 3MM is kept constant. These signatures show a treatment effect of 4.5 MADRS points or more, resulting in a signature advantage of >5 points in 38-63% of patients. Figure 29B shows SigPos=DYN>24.0 or (3MM and DYN>8), corresponding to 63% of the cohort. Figure 29C shows SigPos=DYN>50 or (3MM and DYN>8), corresponding to 38% of the cohort. As shown in Figures 29A-29C, 4 MM biomarker signature positive patients (63% of MDD) responded with a 4.6 MADRS point difference at final DB compared to placebo, a 6 point improvement compared to their biomarker signature negative counterparts.

[0370] Example 5 This is an open-label, multicenter, long-term study to evaluate the efficacy of intranasal esketamine plus a newly initiated oral antidepressant in subjects with TRD (ESKETINTRD3002 / NCT02418585).

[0371] Investigational Drug Information Esketamine was supplied as a clear, colorless intranasal solution of esketamine hydrochloride (16.14% weight / volume [w / v], equivalent to 14% w / v esketamine base) in a nasal spray pump. The solution consisted of 161.4 mg / mL esketamine hydrochloride (equivalent to 140 mg esketamine base) formulated in 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA) and 1.5 mg / mL citric acid (pH 4.5) in water for injection. Provided in a nasal spray pump, the pump delivered 16.14 mg esketamine hydrochloride (14 mg esketamine base) per 100-μL spray. Each individual nasal spray pump (device) contained a total of 28 mg (i.e., two sprays).

[0372] The placebo solution was supplied as a clear, colorless intranasal solution in water for injection, with the addition of a bittering agent (denatonium benzoate [Bitrex™] at a final concentration of 0.001 mg / mL) to simulate the taste of an intranasal solution containing active drug. The placebo solution was provided in a matching nasal spray pump device. Benzalkonium chloride was added at a concentration of 0.3 mg / mL as a preservative. Each individual nasal spray pump (device) contained two doses of spray solution.

[0373] Intranasal investigational drugs Table 33 describes how each intranasal treatment session was administered.

[0374] [Table 43]

[0375] On day 1, subjects randomized to intranasal esketamine started at a dose of 56 mg. On day 4, the dose was increased to 84 mg or remained at 56 mg. On day 8, the dose was increased to 84 mg (if day 4 dose was 56 mg), remained the same, or decreased to 56 mg (if day 4 dose was 84 mg). On day 11, the dose was increased to 84 mg (if day 8 dose was 56 mg), remained the same, or decreased to 56 mg (if day 8 dose was 84 mg). On day 15, dose reduction from 84 mg to 56 mg was allowed if necessary for tolerability. Dose increases were not allowed on day 15. After day 15, the dose remained stable (unchanged).

[0376] Oral antidepressants Duloxetine 30 mg, escitalopram 10 mg, sertraline 50 mg and 25 mg, and venlafaxine 75 mg and 37.5 mg were obtained commercially.

[0377] Treatment duration / trial duration Each subject participated in up to four periods: a maximum 4-week screening period (direct entry subjects only), a 4-week open-label induction (IND) period (direct entry subjects and transferred-in non-responder subjects), a 48-week open-label optimization / maintenance (OP / MA) period (all responder subjects from the open-label IND period of the current study and transferred-in responder subjects), and a 4-week follow-up period. The maximum duration of subject participation in the ESKETINTRD3004 study was 60 weeks for direct entry subjects, 56 weeks for transferred-in non-responder subjects, and 52 weeks for transferred-in responder subjects. A sample size of 750 was estimated such that at least 300 subjects would be treated with intranasal esketamine for 6 months and at least 100 subjects for 12 months. Additionally, transferred-in subjects were enrolled from the 3005 study to obtain 100 elderly subjects receiving esketamine. See Figure 30 for study design.

[0378] Efficacy Analysis Set Efficacy analyses were based on the full (IND) analysis set and the full (OP / MA) analysis set. The full (IND) analysis set was defined as all subjects receiving at least one dose of intranasal study drug or one dose of oral antidepressant during the open-label IND phase (for direct entry and enrolled non-responder subjects). The full (OP / MA) analysis set was defined as all subjects receiving at least one dose of intranasal study drug or one dose of oral antidepressant during the OP / MA phase. Efficacy variables included the 10-item MADRS covering all core depressive symptoms, with each item scored from 0 (no symptoms present or normal) to 6 (severe or persistent presence of symptoms). A total score (0-60) was calculated by adding the scores of all 10 items. Higher scores indicate more severe symptoms.

[0379] Subject and Treatment Information We enrolled 802 subjects with a DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) diagnosis of MDD. Of the 802 enrolled subjects, 691 were direct entry subjects and 111 were transfer-in subjects from study ESKETINTRD3005. Of the 779 direct entry or transfer-in non-responder subjects from the TRD3005 study in the full (IND) analysis population, 580 (74.5%) completed the IND period. Of the 603 subjects who entered the OP / MA period, 150 (24.9%) completed the OP / MA period. A total of 357 subjects entered the follow-up period, and 326 (91.3%) completed the follow-up period.

[0380] Of the 802 enrolled subjects, 1 subject did not receive intranasal study drug but received oral AD, and 1 subject received intranasal study drug but did not receive oral AD. These subjects are included in the All Enrolled Analysis Set. See Tables 34 and 35.

[0381] [Table 44]

[0382] [Table 45]

[0383] Subjects received variable-dose intranasal ESK for the first 2 weeks, followed by a fixed dose (28 mg in older subjects only, 56 mg or 84 mg in all age groups) plus the newly initiated oral antidepressant (sertraline, escitalopram, venlafaxine XR, or fluoxetine). Esketamine was administered twice weekly during the IND. In OP / MA, weekly dosing occurred during weeks 5-8. During weeks 9-52 of the OP / MA phase, esketamine was administered either weekly or biweekly depending on the MADRS score with the aim of having the lowest frequency to maintain remission. Switching to biweekly treatment (if the total MADRS score was ≦12) or returning to weekly treatment (if the total MADRS score was >12) was possible at 4-week intervals starting at week 8. Beginning on Day 15 (patients <65 years) or Day 18 (patients ≥65 years), the dose of esketamine nasal spray remained the same. After an initial period of dose titration, the dose of oral antidepressant remained the same. Dose reductions based on tolerability were permitted for both agents. Baseline psychiatric history for the entire enrolled analysis population is presented in Table 36.

[0384] [Table 46-1]

[0385] [Table 46-2]

[0386] Extent of exposure The number of doses of intranasal investigational drug during the IND period is summarized in Table 37.

[0387] [Table 47]

[0388] A summary of the mean, mode, and final doses of intranasal investigational drug during the IND period are summarized in Table 38. On Day 25 of the IND period, 28 of 675 (4.1%) received a 28 mg dose of esketamine, 298 of 675 (44.1%) received a 56 mg dose of esketamine, and 349 of 675 (51.7%) received an 84 mg dose of esketamine.

[0389] [Table 48]

[0390] The extent of exposure to intranasal investigational drug during the combined IND and OP / MA periods is summarized in Table 39.

[0391] [Table 49]

[0392] The frequency of subjects with 6-month and 12-month exposure to esketamine is shown in Table 40.

[0393] [Table 50]

[0394] A summary of the mean, mode, and final doses of intranasal study drug during the OP / MA period are summarized in Table 41.

[0395] [Table 51]

[0396] At week 48 of the OP / MA phase, 7 of 143 (4.9%), 69 of 143 (48.3%), 1 of 143 (0.7%), and 66 of 143 (46.2%) were receiving 28 mg, 56 mg, 70 mg, and 84 mg doses of esketamine, respectively. Beginning at week 4 (OP / MA), intranasal treatment session frequency was allowed to adjust (if applicable) at fixed 4-week intervals. Of the 603 subjects treated with intranasal esketamine during the OP / MA phase, 275 (47.6%) subjects switched from weekly to biweekly at week 4 (OP / MA). See Table 42.

[0397] [Table 52]

[0398] Table 43 displays the changes in dosing regimen during the OP / MA phase.

[0399] [Table 53]

[0400] Efficacy Analysis Efficacy analyses were performed on the full analysis set of the IND and OP / MA periods, which included all enrolled subjects who received at least one dose of intranasal investigational drug or one dose of oral antidepressant investigational drug in the respective periods.

[0401] Montgomery-Asberg Depression Rating Scale (MADRS) The mean change (SD) from baseline (IND) to endpoint (IND) in MADRS total score was -16.4 (8.76) for esketamine + oral AD. The mean change (SD) from baseline (OP / MA) to endpoint (OP / MA) in MADRS total score was 0.3 (8.12) for esketamine + oral AD. See Figure 31.

[0402] Response rates (≧50% improvement from baseline (IND) in MADRS total score) and remission rates (MADRS total score is ≦12) are presented in Tables 44 and 45 for the IND and OP / MA phases, respectively.

[0403] At the IND end point, the response rate was 78.4% and the remission rate was 47.2%. Of the responders proceeding to the OP / MA end point, 76.5% were responders and 58.2% were remitters at end point. Following functional recovery as measured by SDS, there was some lag time after mood improvement. At the IND end point, the remission rate was measured by SDS at the IND end point (21.1%, observed cases). The remission rate doubled throughout the OP / MA end point (25.2% at week 4 to 51.1% at week 48, observed cases). See Figure 32.

[0404] [Table 54]

[0405] [Table 55]

[0406] Patient Health Questionnaire (PHQ-9) total score The mean change (SD) from baseline (IND) to endpoint (IND) in PHQ-9 total score was -8.9 (6.67) for esketamine + oral AD. The mean change (SD) from baseline (OP / MA) to endpoint (OP / MA) in PHQ-9 total score was -0.2 (5.65) for esketamine + oral AD. See Figure 33.

[0407] Example 6 Venous blood samples were obtained from subjects described in Example 5, as well as from patients and healthy control subjects from other clinical trials referenced herein. Serum or plasma was prepared from venous blood samples. Human CRP and IL-6-R measurements were performed in serum using an MSD Sector 6000 with kits #K151STD and K151ALC (MesoScale Discovery, Rockville, MD). Human TNFα was quantified in serum using a Simoa HD-1 analyzer with kit #143 (Quanterix, Lexington, MA). All measurements were performed according to the kit manufacturer's recommendations.

[0408] As used in the biomarker assay analyses below, treatment (TRT) refers to treatment with intranasal esketamine plus optional oral antidepressant, and placebo (PBO) refers to treatment with placebo plus optional oral antidepressant.

[0409] The following biomarker signatures were used: 3MM: Inflammatory biomarker signature with a positive status defined by CRP>3mg / L and (TNFα>4pg / mL or sIL6R>25ng / mL).

[0410] 2MM: Inflammatory biomarker signature with a positive status defined by CRP>3mg / L and sIL6R>25ng / mL.

[0411] CRP: Inflammatory biomarker signature with positive status defined by CRP>3mg / L.

[0412] The 3MM signature was tested in clinical trials for adjunctive MDD, including treatment-resistant MDD (TRD) and MDD with suicidal ideation (SUI). The effect of 3MM across clinical trials is shown in FIG. 34. Significance was driven by the esketamine (ESK) TRD study. Esketamine TRD shows the strongest effect on hyperinflammatory biotypes (CRP>3mg / L and TNFα>4pg / mL or sIL6R>25ng / mL). In esketamine studies with suicidal ideation (SUI), 3MM status at baseline did not predict treatment effect. Nominally significant (post-hoc, uncorrected for multiple testing) differentiation was found in the esketamine TRD study (see FIG. 35). Colors represent the range of subject n, shapes represent p-values, and grey shaded areas indicate MADRS changes less than 3 points.

[0413] Across esketamine TRD studies, significantly greater treatment effects in biomarker signature positive subjects were evident in three of four studies: 3MM biomarker signature positive subjects (TE Sig Pos , left panel of FIG. 35) improved by 7.8 MADRS points over placebo at the end of double-blind treatment and biomarker signature negative subjects (TE Sig Neg This was a significantly larger (p<0.01) treatment effect than the biomarker signature-negative Japanese patients (p<0.01), who only improved by 2 MADRS points, resulting in a 5.8 point difference between subtypes (signature advantage, right panel of FIG. 35). A larger treatment effect of 11.69 points change in MADRS was also seen in biomarker signature-positive Japanese patients (although n was smaller, FIG. 36A) compared to 2.83 points in biomarker signature-negative Japanese patients (FIG. 36B).

[0414] The same trend was observed across studies when 3MM was reduced to 2MM by removing TNFα and considering only CRP and sIL6R. The following 2MM and CRP analyses also include clinical trials CNTO136MDD2001, 67953964MDD2001, 42847922MDD2001, and 42847922MDD2002, which included administration of sirukumab (CNTO136MDD2001), aticaplant (67953964MDD2001), and seltrexant (42847922MDD2001 and NCT03321526). The overall effect in the biomarker signature positive group (left panel of FIG. 37A and FIG. 37B) is a 4.2 point improvement in MADRS across all studies in 2MM (FIG. 37A) versus 4.6 points in 3MM (FIG. 37B) compared to 1.1 points in the biomarker signature negative group in 2MM (center panel of FIG. 37A and FIG. 37B), with the 1.0 point in 3MM resulting in a 3 point signature advantage in 2MM versus 3.6 points in 3MM (right panel of FIG. 37A and FIG. 37B). Thus, including TNFα in the model optimizes the biomarker signature effect and also captures more n patients. In FIG. 37A, TRD2003 and TRD2003 tend to be non-significant due to flipping the identity of one individual in each study.

[0415] When the model is reduced to CRP levels only, the observed treatment effects for 3MM or 2MM are weaker and more variable. The overall effect in the biomarker signature positive group (left panel of FIG. 38) is a 3.5 point improvement in MADRS over the entire study with CRP only (FIG. 38) versus 4.6 points with 3MM (FIG. 37B), compared to 1.2 points in the biomarker signature negative group with CRP only (center panel of FIG. 38), and the 1.0 point improvement with 3MM results in a signature advantage of only 2.3 points with CRP only versus 3.6 points with 3MM (right panel of FIG. 38). Thus, a single marker (CRP) is not as robust as using a combination of markers. In FIG. 38, TRD3002 is trending due to membership differences for 20 subjects compared to 3MM.

[0416] While the foregoing specification, together with examples given for purposes of illustration, teaches the principles of the invention, it will be understood that the practice of the invention encompasses all ordinary modifications, adaptations and / or alterations that come within the scope of the following claims and equivalents thereto.

Claims

1. A method of treating depression in a human patient comprising administering an effective amount of an antidepressant to the patient in need thereof, wherein the patient is identified as biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

2. The biological sample obtained from the patient a. a level of CRP that is higher than a reference CRP level; and b. i. a level of TNF-α that is higher than a reference TNF-α level, and ii. At least one of a level of sIL6R higher than a reference sIL6R level, wherein the patient is identified as biomarker signature positive.

3. The method of claim 2, wherein the reference CRP level is about 3 mg / L.

3. The method of claim 2, wherein the reference TNF-α level is about 4 pg / mL.

4. 3. The method of claim 2, wherein the reference sIL6R level is about 25 ng / mL.

5. The method according to any one of claims 1 to 4, wherein the antidepressant is selected from esketamine and aticaplant, or a pharma- ceutically acceptable salt thereof.

6. 6. The method of claim 5, wherein the antidepressant is aticaplant, or a pharma- ceutically acceptable salt thereof.

7. 7. The method of claim 6, wherein the patient has had an inadequate response to other antidepressant therapies prior to treatment with aticaplant or a pharma- ceutically acceptable salt thereof.

8. 8. The method of claim 7, wherein the other antidepressant therapy includes one or more second antidepressants.

9. 9. The method of claim 8, wherein the one or more second antidepressants comprises a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI) therapy, or a combination thereof.

10. The method of any one of claims 1 to 9, wherein the patient has anhedonia.

11. 11. The method of claim 10, wherein the patient has a total score of ≧32 on the Snaith Hamilton Pleasure Scale (SHAPS).

12. 12. The method of any one of claims 1 to 11, further comprising adjunctive treatment with an effective amount of one or more second antidepressants.

13. 13. The method of claim 12, wherein the one or more second antidepressants is a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

14. 7. The method of claim 6, wherein the aticaplant is S-aticaplant, or a pharma- ceutically acceptable salt thereof.

15. 7. The method of claim 6, wherein the effective amount of aticaplant is from about 2 to about 35 mg.

16. 16. The method of claim 15, wherein the effective amount of aticaplant is about 10 mg.

17. 16. The method of claim 15, wherein the effective amount of aticaplant is about 5 mg.

18. The method of claim 6 , wherein the aticaplant is administered orally.

19. 7. The method of claim 6, wherein the aticaplant is administered once a day.

20. 7. The method of claim 6, wherein the antidepressant is esketamine.

21. 21. The method of claim 20, having an induction phase and, optionally, a subsequent maintenance phase, the induction phase including induction phase treatment sessions at a given frequency and the maintenance phase including maintenance phase treatment sessions administered less frequently to the patient.

22. a. intranasally administering to said patient about 28 mg to about 84 mg of esketamine per induction phase treatment session, said induction phase treatment sessions occurring at a frequency of twice weekly during said induction phase; and optionally, b. The method of claim 21, comprising intranasally administering about 56 mg to about 84 mg of esketamine to said patient per maintenance treatment session, said maintenance treatment session occurring once a week or once every other week.

23. 23. The method of claim 21 or 22, wherein the induction phase has a duration of about 4 weeks.

24. 25. The method of any one of claims 21-24, wherein about 56 or about 84 mg of esketamine is administered per induction phase treatment session.

25. 25. The method of claim 24, wherein about 56 or about 84 mg of esketamine is administered per maintenance treatment session.

26. 26. The method of any one of claims 21-25, wherein the esketamine is delivered from an intranasal device in two or more sprays during the induction phase and / or the maintenance phase.

27. 27. The method of any one of claims 20 to 26, further comprising administering to the patient a therapeutically effective amount of an oral antidepressant during the induction phase and / or the maintenance phase.

28. 28. The method of any one of claims 21 to 27, wherein the esketamine is administered as its corresponding hydrochloride salt during the induction phase and / or the maintenance phase.

29. The method of any one of claims 1 to 28, wherein the depression comprises major depressive disorder.

30. 30. The method of claim 29, wherein the major depressive disorder is major depressive disorder accompanied by suicidal ideation or behavior.

31. 30. The method of claim 29, wherein the major depressive disorder is treatment-resistant depression.

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